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1
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Li K, Wang H, Jiang B, Jin X. The impact of dysregulation SUMOylation on prostate cancer. J Transl Med 2025; 23:286. [PMID: 40050932 PMCID: PMC11887156 DOI: 10.1186/s12967-025-06271-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2025] [Accepted: 02/18/2025] [Indexed: 03/09/2025] Open
Abstract
Prostate cancer (PCa) remains one of the most common malignancies in men, with its development and progression being governed by complex molecular pathways. SUMOylation, a post-translational modification (PTM) that involves the covalent attachment of small ubiquitin-like modifier (SUMO) proteins to target substrates, has emerged as a critical regulator of various cellular processes such as transcription, DNA repair, cell cycle progression, and apoptosis. Emerging evidence reveals that abnormal SUMOylation may contribute to PCa pathogenesis, and notably, SUMO-associated enzymes are commonly dysregulated in PCa. This review explores the mechanisms by which SUMOylation is implicated in the regulation of key pathways, and summary aberrant expression of SUMO-related enzymes or SUMOylation sites mutations of substrtes in PCa, as well as the therapeutic implications of targeting the SUMO-related enzymes in PCa treatment.
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Affiliation(s)
- Kailang Li
- Department of Oncology, Beilun Branch of the First Affiliated Hospital, College of Medicine, Zhejiang University, Ningbo, 315826, China
- Department of Oncology, Beilun District People's Hospital, Ningbo, 315826, China
| | - Haifeng Wang
- Department of Oncology, Beilun Branch of the First Affiliated Hospital, College of Medicine, Zhejiang University, Ningbo, 315826, China
- Department of Oncology, Beilun District People's Hospital, Ningbo, 315826, China
| | - Bitao Jiang
- Department of Oncology, Beilun Branch of the First Affiliated Hospital, College of Medicine, Zhejiang University, Ningbo, 315826, China.
- Department of Oncology, Beilun District People's Hospital, Ningbo, 315826, China.
| | - Xiaofeng Jin
- Department of Biochemistry and Molecular Biology, Zhejiang Key Laboratory of Pathphysiology, Health Science Center, Ningbo University, Ningbo, 315211, China.
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2
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van Wier SP, Beekman AM. Peptide design to control protein-protein interactions. Chem Soc Rev 2025; 54:1684-1698. [PMID: 39817557 PMCID: PMC11736853 DOI: 10.1039/d4cs00243a] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2024] [Indexed: 01/18/2025]
Abstract
Targeting of protein-protein interactions has become of huge interest in every aspect of medicinal and biological sciences. The control of protein interactions selectively offers the opportunity to control biological processes while limiting off target effects. This interest has massively increased with the development of cryo-EM and protein structure prediction with tools such as RosettaFold and AlphaFold. When designing molecules to control protein interactions, either inhibition or stabilisation, a starting point is commonly peptide design. This tutorial review describes that process, highlighting the selection of an initial sequence with and without structural information. Subsequently, methods for how the sequence can be analysed for key residues and how this information can be used to optimise the ligand efficiency are highlighted. Finally a discussion on how peptides can be further modified to increase their affinity and cell permeability, improving their drug-like properties, is presented.
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Affiliation(s)
- Suzanne P van Wier
- School of Chemistry, Pharmacy & Pharmacology, University of East Anglia, Norwich Research Park, Norwich, NR4 7TJ, UK.
| | - Andrew M Beekman
- School of Chemistry, Pharmacy & Pharmacology, University of East Anglia, Norwich Research Park, Norwich, NR4 7TJ, UK.
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3
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Dong S, Ye C, Li B, Lv F, Zhang L, Yang S, Wang F, Zhu M, Zhou M, Guo F, Li Z, Peng L, Ji C, Lu X, Cheng Y, Ren X, Chen Y, Zhou J, Yang J, Zhang Y. Targeting of Tumoral NAC1 Mitigates Myeloid-Derived Suppressor Cell-Mediated Immunosuppression and Potentiates Anti-PD-1 Therapy in Ovarian Cancer. Cancer Immunol Res 2025; 13:286-302. [PMID: 39531476 DOI: 10.1158/2326-6066.cir-24-0084] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2024] [Revised: 06/01/2024] [Accepted: 11/12/2024] [Indexed: 11/16/2024]
Abstract
Epithelial ovarian cancer is the most common type of ovarian cancer with a low rate of response to immunotherapy such as immune checkpoint blockade therapy. In this study, we report that nucleus accumbens-associated protein 1 (NAC1), a putative driver of epithelial ovarian cancer, has a critical role in immune evasion. We showed in murine ovarian cancer models that depleting or inhibiting tumoral NAC1 reduced the recruitment and immunosuppressive function of myeloid-derived suppressor cells (MDSC) in the tumor microenvironment, led to significant increases of cytotoxic tumor-infiltrating CD8+ T cells, and promoted antitumor immunity and suppressed tumor progression. We further showed that tumoral NAC1 directly enhanced the transcription of CXCL16 by binding to CXCR6, thereby promoting MDSC recruitment to the tumor. Moreover, lipid C20:1T produced by NAC1-expressing tumor cells fueled oxidative metabolism of MDSCs and promoted their immune-suppressive function. We also showed that NIC3, a small-molecule inhibitor of NAC1, was able to sensitize mice bearing NAC1-expressing ovarian tumors to anti-PD-1 therapy. Our study reveals a critical role for NAC1 in controlling tumor infiltration of MDSCs and in modulating the efficacy of immune checkpoint blockade therapy. Thus, targeting of NAC1 may be exploited to sensitize ovarian cancer to immunotherapy.
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Affiliation(s)
- Shunli Dong
- Center of Translational Medicine, First People's Hospital of Taicang City, Taicang Affiliated Hospital of Soochow University, Taicang, China
- Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou, China
| | - Cong Ye
- Center of Translational Medicine, First People's Hospital of Taicang City, Taicang Affiliated Hospital of Soochow University, Taicang, China
- Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou, China
| | - Bin Li
- Department of Central Laboratory, Suzhou Ninth Hospital Affiliated to Soochow University, Soochow University, Suzhou, China
| | - Fanglin Lv
- Center of Translational Medicine, First People's Hospital of Taicang City, Taicang Affiliated Hospital of Soochow University, Taicang, China
- Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou, China
| | - Lu Zhang
- Center of Translational Medicine, First People's Hospital of Taicang City, Taicang Affiliated Hospital of Soochow University, Taicang, China
- Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou, China
| | - Shumin Yang
- Center of Translational Medicine, First People's Hospital of Taicang City, Taicang Affiliated Hospital of Soochow University, Taicang, China
- Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou, China
| | - Fang Wang
- Department of Gynecology and Obstetrics, First Affiliated Hospital, Soochow University, Suzhou, China
| | - Mingxian Zhu
- Center of Translational Medicine, First People's Hospital of Taicang City, Taicang Affiliated Hospital of Soochow University, Taicang, China
- Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou, China
| | - Mingxuan Zhou
- Center of Translational Medicine, First People's Hospital of Taicang City, Taicang Affiliated Hospital of Soochow University, Taicang, China
- Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou, China
| | - Fanfan Guo
- Center of Translational Medicine, First People's Hospital of Taicang City, Taicang Affiliated Hospital of Soochow University, Taicang, China
- Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou, China
| | - Zhenyun Li
- Center of Translational Medicine, First People's Hospital of Taicang City, Taicang Affiliated Hospital of Soochow University, Taicang, China
- Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou, China
| | - Lei Peng
- Center of Translational Medicine, First People's Hospital of Taicang City, Taicang Affiliated Hospital of Soochow University, Taicang, China
- Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou, China
| | - Cheng Ji
- Department of Respiratory Medicine, First Affiliated Hospital, Soochow University, Suzhou, China
| | - Xialiang Lu
- Department of Pathology, Suzhou Ninth Hospital Affiliated to Soochow University, Soochow University, Suzhou, China
| | - Yan Cheng
- Center of Translational Medicine, First People's Hospital of Taicang City, Taicang Affiliated Hospital of Soochow University, Taicang, China
- Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou, China
| | - Xingcong Ren
- Department of Cancer Biology and Toxicology, Markey Cancer Center, College of Medicine, University of Kentucky, Lexington, Kentucky
| | - Youguo Chen
- Department of Gynecology and Obstetrics, First Affiliated Hospital, Soochow University, Suzhou, China
| | - Jinhua Zhou
- Department of Gynecology and Obstetrics, First Affiliated Hospital, Soochow University, Suzhou, China
| | - Jinming Yang
- Department of Cancer Biology and Toxicology, Markey Cancer Center, College of Medicine, University of Kentucky, Lexington, Kentucky
| | - Yi Zhang
- Center of Translational Medicine, First People's Hospital of Taicang City, Taicang Affiliated Hospital of Soochow University, Taicang, China
- Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou, China
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4
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Zhang Y, Zhong L, Wan P, Zhao Y, Wang M, Zhang H, Liao Y, Deng Y, Liu B. NACC1 accelerates the progression of AML by regulating the ADAM9/PI3K/AKT axis. Int J Med Sci 2025; 22:630-640. [PMID: 39898241 PMCID: PMC11783076 DOI: 10.7150/ijms.102266] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/12/2024] [Accepted: 12/12/2024] [Indexed: 02/04/2025] Open
Abstract
Nucleus accumbens-associated protein 1 (NACC1) regulates various types of biological processes. It is a transcription factor associated with cancer. NACC1 is overexpressed in many human malignancies and can regulate the progression, metastasis, and drug resistance of cancer cells. However, its precise role in acute myeloid leukemia (AML) remains unknown. This study aimed to unravel the basic mechanism of NACC1 in AML. Our findings demonstrated that NACC1 is immensely expressed in AML cells. Lentiviral vector-mediated knockdown of NACC1 inhibited the PI3K/AKT signaling pathway. Simultaneously, NACC1 knockdown promoted apoptosis, suppressed the proliferative capacity of AML cells, and resulted in cell cycle arrest during the G0/G1 phase. Additionally, A disintegrin and metalloproteinase 9 (ADAM9) was markedly expressed in AML cells. NACC1 regulated ADAM9 expression. ADAM9 expression was also downregulated after NACC1 knockdown. Concurrently, ADAM9 knockdown affected the activity of AML cells by decelerating the growth rate, promoting apoptosis, and blocking cell cycle progression. In addition, the AKT activator SC79 restored the inhibited cell proliferation after NACC1 knockdown and ADAM9 knockdown. In conclusion, our study suggested that the NACC1/ADAM9/PI3K/AKT axis is crucial for sustaining the survival of AML cells, indicating that NACC1 may be a viable target for treating AML.
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Affiliation(s)
- Ying Zhang
- Central Laboratory of Yongchuan Hospital, Chongqing Medical University, Chongqing 402160, China
| | - Liang Zhong
- Key Laboratory of Laboratory Medical Diagnostics, Ministry of Education, Department of Laboratory Medicine, Chongqing Medical University, Chongqing 400016, China
| | - Peng Wan
- Central Laboratory of Yongchuan Hospital, Chongqing Medical University, Chongqing 402160, China
| | - Yi Zhao
- Central Laboratory of Yongchuan Hospital, Chongqing Medical University, Chongqing 402160, China
| | - Meng Wang
- Central Laboratory of Yongchuan Hospital, Chongqing Medical University, Chongqing 402160, China
| | - Hongyan Zhang
- Central Laboratory of Yongchuan Hospital, Chongqing Medical University, Chongqing 402160, China
| | - Yang Liao
- Central Laboratory of Yongchuan Hospital, Chongqing Medical University, Chongqing 402160, China
| | - Ying Deng
- Central Laboratory of Yongchuan Hospital, Chongqing Medical University, Chongqing 402160, China
| | - Beizhong Liu
- Central Laboratory of Yongchuan Hospital, Chongqing Medical University, Chongqing 402160, China
- Key Laboratory of Laboratory Medical Diagnostics, Ministry of Education, Department of Laboratory Medicine, Chongqing Medical University, Chongqing 400016, China
- Clinical Laboratory of The Affiliated Rehabilitation Hospital, Chongqing Medical University, Chongqing 400050, China
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5
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Ngule C, Shi R, Ren X, Jia H, Oyelami F, Li D, Park Y, Kim J, Hemati H, Zhang Y, Xiong X, Shinkle A, Vanderford NL, Bachert S, Zhou BP, Wang J, Song J, Liu X, Yang JM. NAC1 promotes stemness and regulates myeloid-derived cell status in triple-negative breast cancer. Mol Cancer 2024; 23:188. [PMID: 39243032 PMCID: PMC11378519 DOI: 10.1186/s12943-024-02102-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2024] [Accepted: 08/27/2024] [Indexed: 09/09/2024] Open
Abstract
Triple negative breast cancer (TNBC) is a particularly lethal breast cancer (BC) subtype driven by cancer stem cells (CSCs) and an immunosuppressive microenvironment. Our study reveals that nucleus accumbens associated protein 1 (NAC1), a member of the BTB/POZ gene family, plays a crucial role in TNBC by maintaining tumor stemness and influencing myeloid-derived suppressor cells (MDSCs). High NAC1 expression correlates with worse TNBC prognosis. NAC1 knockdown reduced CSC markers and tumor cell proliferation, migration, and invasion. Additionally, NAC1 affects oncogenic pathways such as the CD44-JAK1-STAT3 axis and immunosuppressive signals (TGFβ, IL-6). Intriguingly, the impact of NAC1 on tumor growth varies with the host immune status, showing diminished tumorigenicity in natural killer (NK) cell-competent mice but increased tumorigenicity in NK cell-deficient ones. This highlights the important role of the host immune system in TNBC progression. In addition, high NAC1 level in MDSCs also supports TNBC stemness. Together, this study implies NAC1 as a promising therapeutic target able to simultaneously eradicate CSCs and mitigate immune evasion.
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Affiliation(s)
- Chrispus Ngule
- Department of Toxicology and Cancer Biology, Department of Pharmacology and Nutritional Science, and Markey Cancer Center, University of Kentucky College of Medicine, Lexington, KY, 40536, USA
| | - Ruyi Shi
- Department of Toxicology and Cancer Biology, Department of Pharmacology and Nutritional Science, and Markey Cancer Center, University of Kentucky College of Medicine, Lexington, KY, 40536, USA
- Present Address: Department of Cell Biology and Genetics, Shanxi Medical University, Taiyuan, Shanxi, China
| | - Xingcong Ren
- Department of Toxicology and Cancer Biology, Department of Pharmacology and Nutritional Science, and Markey Cancer Center, University of Kentucky College of Medicine, Lexington, KY, 40536, USA
| | - Hongyan Jia
- Department of Toxicology and Cancer Biology, Department of Pharmacology and Nutritional Science, and Markey Cancer Center, University of Kentucky College of Medicine, Lexington, KY, 40536, USA
- Present Address: Department of Breast Surgery, First Hospital of Shanxi Medical University, Taiyuan, Shanxi, China
| | - Felix Oyelami
- Department of Toxicology and Cancer Biology, Department of Pharmacology and Nutritional Science, and Markey Cancer Center, University of Kentucky College of Medicine, Lexington, KY, 40536, USA
| | - Dong Li
- Department of Toxicology and Cancer Biology, Department of Pharmacology and Nutritional Science, and Markey Cancer Center, University of Kentucky College of Medicine, Lexington, KY, 40536, USA
| | - Younhee Park
- Department of Toxicology and Cancer Biology, Department of Pharmacology and Nutritional Science, and Markey Cancer Center, University of Kentucky College of Medicine, Lexington, KY, 40536, USA
| | - Jinhwan Kim
- Department of Biochemistry, and Markey Cancer Center, University of Kentucky College of Medicine, Lexington, KY, 40536, USA
| | - Hami Hemati
- Department of Toxicology and Cancer Biology, Department of Pharmacology and Nutritional Science, and Markey Cancer Center, University of Kentucky College of Medicine, Lexington, KY, 40536, USA
| | - Yi Zhang
- Department of Toxicology and Cancer Biology, Department of Pharmacology and Nutritional Science, and Markey Cancer Center, University of Kentucky College of Medicine, Lexington, KY, 40536, USA
- Present Address: Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu, China
| | - Xiaofang Xiong
- Department of Microbial Pathogenesis and Immunology, Texas A&M University Health Science Center, Bryan, TX, 77807, USA
| | - Andrew Shinkle
- Department of Toxicology and Cancer Biology, Department of Pharmacology and Nutritional Science, and Markey Cancer Center, University of Kentucky College of Medicine, Lexington, KY, 40536, USA
| | - Nathan L Vanderford
- Department of Toxicology and Cancer Biology, Department of Pharmacology and Nutritional Science, and Markey Cancer Center, University of Kentucky College of Medicine, Lexington, KY, 40536, USA
| | - Sara Bachert
- Department of Pathology and Laboratory Medicine, University of Kentucky, Lexington, KY, 40536, USA
| | - Binhua P Zhou
- Department of Biochemistry, and Markey Cancer Center, University of Kentucky College of Medicine, Lexington, KY, 40536, USA
| | - Jianlong Wang
- Department of Medicine, Columbia Center for Human Development and Stem Cell Therapies, Columbia University Irving Medical Center, New York, NY, 10032, USA
| | - Jianxun Song
- Department of Microbial Pathogenesis and Immunology, Texas A&M University Health Science Center, Bryan, TX, 77807, USA.
| | - Xia Liu
- Department of Toxicology and Cancer Biology, Department of Pharmacology and Nutritional Science, and Markey Cancer Center, University of Kentucky College of Medicine, Lexington, KY, 40536, USA.
| | - Jin-Ming Yang
- Department of Toxicology and Cancer Biology, Department of Pharmacology and Nutritional Science, and Markey Cancer Center, University of Kentucky College of Medicine, Lexington, KY, 40536, USA.
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Hissong E, Assaad MA, Bal M, Reed KA, Fornelli A, Levine MF, Gundem G, Semaan A, Orr CE, Sakhadeo U, Manohar J, Sigouros M, Wilkes D, Sboner A, Montgomery EA, Graham RP, Medina-Martínez JS, Robine N, Fang JM, Choi EYK, Westerhoff M, la Mora JDD, Caudell P, Yantiss RK, Papaemmanuil E, Elemento O, Sigel C, Jessurun J, Mosquera JM. NIPBL::NACC1 Fusion Hepatic Carcinoma. Am J Surg Pathol 2024; 48:183-193. [PMID: 38047392 PMCID: PMC11238093 DOI: 10.1097/pas.0000000000002159] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/05/2023]
Abstract
Several reports describing a rare primary liver tumor with histologic features reminiscent of follicular thyroid neoplasms have been published under a variety of descriptive terms including thyroid-like, solid tubulocystic, and cholangioblastic cholangiocarcinoma. Although these tumors are considered to represent histologic variants, they lack classic features of cholangiocarcinoma and have unique characteristics, namely immunoreactivity for inhibin and NIPBL::NACC1 fusions. The purpose of this study is to present clinicopathologic and molecular data for a large series of these tumors to better understand their pathogenesis. We identified 11 hepatic tumors with these features. Immunohistochemical and NACC1 and NIPBL fluorescence in situ hybridization assays were performed on all cases. Four cases had available material for whole-genome sequencing (WGS) analysis. Most patients were adult women (mean age: 42 y) who presented with abdominal pain and large hepatic masses (mean size: 14 cm). Ten patients had no known liver disease. Of the patients with follow-up information, 3/9 (33%) pursued aggressive behavior. All tumors were composed of bland cuboidal cells with follicular and solid/trabecular growth patterns in various combinations, were immunoreactive for inhibin, showed albumin mRNA by in situ hybridization, and harbored the NIPBL::NACC1 fusion by fluorescence in situ hybridization. WGS corroborated the presence of the fusion in all 4 tested cases, high tumor mutational burden in 2 cases, and over 30 structural variants per case in 3 sequenced tumors. The cases lacked mutations typical of conventional intrahepatic cholangiocarcinoma. In this report, we describe the largest series of primary inhibin-positive hepatic neoplasms harboring a NIPBL::NACC1 fusion and the first WGS analysis of these tumors. We propose to name this neoplasm NIPBL:NACC1 fusion hepatic carcinoma.
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Affiliation(s)
- Erika Hissong
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY
| | - Majd Al Assaad
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY
- Englander Institute for Precision Medicine, Weill Cornell Medicine and New York Presbyterian, New York, NY
| | - Munita Bal
- Department of Pathology, Tata Memorial Centre, Mumbai, India
| | - Katelyn A. Reed
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN
| | - Adele Fornelli
- U.O. Anatomia Patologica, Ospedale Maggiore, Bologna, Italy
| | | | | | - Alissa Semaan
- Englander Institute for Precision Medicine, Weill Cornell Medicine and New York Presbyterian, New York, NY
| | - Christine E. Orr
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY
| | - Uma Sakhadeo
- Department of Pathology, Tata Memorial Centre, Mumbai, India
| | - Jyothi Manohar
- Englander Institute for Precision Medicine, Weill Cornell Medicine and New York Presbyterian, New York, NY
| | - Michael Sigouros
- Englander Institute for Precision Medicine, Weill Cornell Medicine and New York Presbyterian, New York, NY
| | - David Wilkes
- Englander Institute for Precision Medicine, Weill Cornell Medicine and New York Presbyterian, New York, NY
| | - Andrea Sboner
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY
- Englander Institute for Precision Medicine, Weill Cornell Medicine and New York Presbyterian, New York, NY
- Institute for Computational Biomedicine, Weill Cornell Medicine, New York, NY
| | - Elizabeth A. Montgomery
- Department of Pathology and Laboratory Medicine, University of Miami Hospital (UMH), Miami, FL
| | - Rondell P. Graham
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN
| | | | | | - Jiayun M Fang
- Department of Pathology, University of Michigan, Ann Arbor, MI
| | | | | | - Jesus Delgado-de la Mora
- Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran, Ciudad de México, CDMX, Mexico
| | | | - Rhonda K. Yantiss
- Department of Pathology and Laboratory Medicine, University of Miami Hospital (UMH), Miami, FL
| | | | - Olivier Elemento
- Englander Institute for Precision Medicine, Weill Cornell Medicine and New York Presbyterian, New York, NY
- Department of Physiology and Biophysics, Weill Cornell Medicine, New York, NY
- Institute for Computational Biomedicine, Weill Cornell Medicine, New York, NY
| | - Carlie Sigel
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY
| | - José Jessurun
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY
| | - Juan Miguel Mosquera
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY
- Englander Institute for Precision Medicine, Weill Cornell Medicine and New York Presbyterian, New York, NY
- New York Genome Center, New York, NY
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7
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Wang Y, Douville C, Chien YW, Wang BG, Chen CL, Pinto A, Smith SA, Drapkin R, Chui MH, Numan T, Vang R, Papadopoulos N, Wang TL, Shih IM. Aneuploidy Landscape in Precursors of Ovarian Cancer. Clin Cancer Res 2024; 30:600-615. [PMID: 38048050 DOI: 10.1158/1078-0432.ccr-23-0932] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2023] [Revised: 07/21/2023] [Accepted: 11/27/2023] [Indexed: 12/05/2023]
Abstract
PURPOSE Serous tubal intraepithelial carcinoma (STIC) is now recognized as the main precursor of ovarian high-grade serous carcinoma (HGSC). Other potential tubal lesions include p53 signatures and tubal intraepithelial lesions. We aimed to investigate the extent and pattern of aneuploidy in these epithelial lesions and HGSC to define the features that characterize stages of tumor initiation and progression. EXPERIMENTAL DESIGN We applied RealSeqS to compare genome-wide aneuploidy patterns among the precursors, HGSC (cases, n = 85), and histologically unremarkable fallopian tube epithelium (HU-FTE; control, n = 65). On the basis of a discovery set (n = 67), we developed an aneuploidy-based algorithm, REAL-FAST (Repetitive Element AneupLoidy Sequencing Fallopian Tube Aneuploidy in STIC), to correlate the molecular data with pathology diagnoses. We validated the result in an independent validation set (n = 83) to determine its performance. We correlated the molecularly defined precursor subgroups with proliferative activity and histology. RESULTS We found that nearly all p53 signatures lost the entire Chr17, offering a "two-hit" mechanism involving both TP53 and BRCA1 in BRCA1 germline mutation carriers. Proliferatively active STICs harbor gains of 19q12 (CCNE1), 19q13.2, 8q24 (MYC), or 8q arm, whereas proliferatively dormant STICs show 22q loss. REAL-FAST classified HU-FTE and STICs into 5 clusters and identified a STIC subgroup harboring unique aneuploidy that is associated with increased proliferation and discohesive growth. On the basis of a validation set, REAL-FAST showed 95.8% sensitivity and 97.1% specificity in detecting STIC/HGSC. CONCLUSIONS Morphologically similar STICs are molecularly distinct. The REAL-FAST assay identifies a potentially "aggressive" STIC subgroup harboring unique DNA aneuploidy that is associated with increased cellular proliferation and discohesive growth. REAL-FAST offers a highly reproducible adjunct technique to assist the diagnosis of STIC lesions.
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Affiliation(s)
- Yeh Wang
- Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, Maryland
| | - Christopher Douville
- Department of Oncology, the Sidney Kimmel Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland
- The Ludwig Center, Johns Hopkins University School of Medicine, Baltimore, Maryland
- The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins Medical Institutions, Baltimore, Maryland
| | - Yen-Wei Chien
- Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, Maryland
| | - Brant G Wang
- Department of Pathology, Inova Fairfax Hospital, Falls Church, Virginia
- School of Medicine Inova Campus, University of Virginia, Falls Church, Virginia
- Department of Pathology, Georgetown University Medical Center, Washington, DC
| | - Chi-Long Chen
- Department of Pathology, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Andre Pinto
- University of Miami Sylvester Comprehensive Cancer Center, Miami, Florida
| | - Saron Ann Smith
- Cascade Pathology Services, Legacy Health System, Portland, Oregon
| | - Ronny Drapkin
- Department of Obstetrics and Gynecology and Basser Center for BRCA, University of Pennsylvania, Philadelphia, Pennsylvania
| | - M Herman Chui
- Department of Pathology and Laboratory Medicine, Sloan-Kettering Cancer Center, New York, New York
| | - Tricia Numan
- Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, Maryland
- Department of Pathology, Sibley Memorial Hospital, Washington, DC
| | - Russell Vang
- Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, Maryland
| | - Nickolas Papadopoulos
- Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, Maryland
- Department of Oncology, the Sidney Kimmel Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland
- The Ludwig Center, Johns Hopkins University School of Medicine, Baltimore, Maryland
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins Medical Institutions, Baltimore, Maryland
| | - Tian-Li Wang
- Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, Maryland
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins Medical Institutions, Baltimore, Maryland
- Department of Gynecology and Obstetrics, Johns Hopkins Medical Institutions, Baltimore, Maryland
| | - Ie-Ming Shih
- Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, Maryland
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins Medical Institutions, Baltimore, Maryland
- Department of Gynecology and Obstetrics, Johns Hopkins Medical Institutions, Baltimore, Maryland
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Xie Q, Tong C, Xiong X. An overview of the co-transcription factor NACC1: Beyond its pro-tumor effects. Life Sci 2024; 336:122314. [PMID: 38030057 DOI: 10.1016/j.lfs.2023.122314] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2023] [Revised: 11/20/2023] [Accepted: 11/26/2023] [Indexed: 12/01/2023]
Abstract
Nucleus accumbens-associated protein 1 (NACC1) is a member of the broad complex, tramtrack, bric-a-brac/poxvirus and zinc finger (BTB/POZ) protein families, mainly exerting its biological functions as a transcription co-regulator. NACC1 forms homo- or hetero-dimers through the BTB/POZ or BANP, E5R, and NACC1 (BEN) domain with other transcriptional regulators to regulate downstream signals. Recently, the overexpression of NACC1 has been observed in various tumors and is positively associated with tumor progression, high recurrence rate, indicating poor prognosis. NACC1 also regulates biological processes such as embryonic development, stem cell pluripotency, innate immunity, and related diseases. Our review combines recent research to summarize advancements in the structure, biological functions, and relative molecular mechanisms of NACC1. The future development of NACC1 clinical appliances is also discussed.
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Affiliation(s)
- Qing Xie
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Nanchang University, Nanchang, 330006, China; School of Basic Medical Sciences, Nanchang University, Nanchang, 330006, China
| | - Chang Tong
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Nanchang University, Nanchang, 330006, China
| | - Xiangyang Xiong
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Nanchang University, Nanchang, 330006, China; Province Key Laboratory of Tumor Pathogens and Molecular Pathology, Nanchang University, Nanchang 330006, China.
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9
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González IA, Luo W, Zhang X. Solid-Tubulocystic carcinoma: A new variant of intrahepatic cholangiocarcinoma. World J Hepatol 2023; 15:897-903. [PMID: 37547028 PMCID: PMC10401414 DOI: 10.4254/wjh.v15.i7.897] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2023] [Revised: 06/07/2023] [Accepted: 06/13/2023] [Indexed: 07/21/2023] Open
Abstract
A new variant of intrahepatic cholangiocarcinoma (iCCA) has been recognized in recent years presenting predominantly as a large hepatic mass in young woman with the characteristic expression of inhibin by immunohistochemistry. This variant iCCA was originally termed as cholangioblastic variant of iCCA, and subsequently proposed to be renamed as inhibin-positive hepatic carcinoma or solid-tubulocystic variant of iCCA to better reflect its immunohistochemical profile or morphologic spectrum. The tumor histologically is composed of small to medium sized cells with scant to moderate amount of eosinophilic cytoplasm heterogeneously organized in solid, tubular, and cystic growth patterns. The tumor cells are positive for biliary markers, inhibin and albumin, and have a novel recurrent gene fusion, NIPBL::NACC1. Awareness of this new iCCA variant and its clinicopathologic features will aid in the diagnostic work-up and avoid confusion with other primary and metastatic hepatic neoplasms.
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Affiliation(s)
- Iván A González
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, IN 46202, United States
| | - Wenyi Luo
- Department of Pathology, Yale University School of Medicine, New Haven, CT 06511, United States
| | - Xuchen Zhang
- Department of Pathology, Yale University School of Medicine, New Haven, CT 06511, United States.
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10
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Ngule CM, Hemati H, Ren X, Obaleye O, Akinyemi AO, Oyelami FF, Xiong X, Song J, Liu X, Yang JM. Identification of a NACC1-Regulated Gene Signature Implicated in the Features of Triple-Negative Breast Cancer. Biomedicines 2023; 11:1223. [PMID: 37189841 PMCID: PMC10136325 DOI: 10.3390/biomedicines11041223] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2023] [Revised: 04/05/2023] [Accepted: 04/12/2023] [Indexed: 05/17/2023] Open
Abstract
Triple-negative breast cancer (TNBC), characterized by a deficiency in estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor2 (HER2), is among the most lethal subtypes of breast cancer (BC). Nevertheless, the molecular determinants that contribute to its malignant phenotypes such as tumor heterogeneity and therapy resistance, remain elusive. In this study, we sought to identify the stemness-associated genes involved in TNBC progression. Using bioinformatics approaches, we found 55 up- and 9 downregulated genes in TNBC. Out of the 55 upregulated genes, a 5 gene-signature (CDK1, EZH2, CCNB1, CCNA2, and AURKA) involved in cell regeneration was positively correlated with the status of tumor hypoxia and clustered with stemness-associated genes, as recognized by Parametric Gene Set Enrichment Analysis (PGSEA). Enhanced infiltration of immunosuppressive cells was also positively correlated with the expression of these five genes. Moreover, our experiments showed that depletion of the transcriptional co-factor nucleus accumbens-associated protein 1 (NAC1), which is highly expressed in TNBC, reduced the expression of these genes. Thus, the five genes signature identified by this study warrants further exploration as a potential new biomarker of TNBC heterogeneity/stemness characterized by high hypoxia, stemness enrichment, and immune-suppressive tumor microenvironment.
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Affiliation(s)
- Chrispus M. Ngule
- Department of Toxicology and Cancer Biology, College of Medicine, University of Kentucky, Lexington, KY 40536, USA
| | - Hami Hemati
- Department of Toxicology and Cancer Biology, College of Medicine, University of Kentucky, Lexington, KY 40536, USA
| | - Xingcong Ren
- Department of Toxicology and Cancer Biology, College of Medicine, University of Kentucky, Lexington, KY 40536, USA
| | - Oluwafunminiyi Obaleye
- Department of Toxicology and Cancer Biology, College of Medicine, University of Kentucky, Lexington, KY 40536, USA
| | - Amos O. Akinyemi
- Department of Toxicology and Cancer Biology, College of Medicine, University of Kentucky, Lexington, KY 40536, USA
| | - Felix F. Oyelami
- Department of Toxicology and Cancer Biology, College of Medicine, University of Kentucky, Lexington, KY 40536, USA
| | - Xiaofang Xiong
- Department of Microbial Pathogenesis and Immunology, Texas A&M University Health Science Center, Bryan, TX 77807, USA
| | - Jianxun Song
- Department of Microbial Pathogenesis and Immunology, Texas A&M University Health Science Center, Bryan, TX 77807, USA
| | - Xia Liu
- Department of Toxicology and Cancer Biology, College of Medicine, University of Kentucky, Lexington, KY 40536, USA
- Markey Cancer Center, College of Medicine, University of Kentucky, Lexington, KY 40536, USA
| | - Jin-Ming Yang
- Department of Toxicology and Cancer Biology, College of Medicine, University of Kentucky, Lexington, KY 40536, USA
- Markey Cancer Center, College of Medicine, University of Kentucky, Lexington, KY 40536, USA
- Department of Pharmacology and Nutritional Science, College of Medicine, University of Kentucky, Lexington, KY 40536, USA
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11
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Dong S, Wang X, Yang S, Guo F, Zhang J, Ji C, Shi L, Cheng Y, Hu Y, Li Z, Peng L, Guo L, Zhu W, Ren X, Yang JM, Zhang Y. Mechanistic Insights of NAC1 Nuclear Export and Its Role in Ovarian Cancer Resistance to Docetaxel. Biochem Pharmacol 2023; 211:115533. [PMID: 37019189 DOI: 10.1016/j.bcp.2023.115533] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2023] [Revised: 03/14/2023] [Accepted: 03/28/2023] [Indexed: 04/05/2023]
Abstract
In this study, we uncovered the nuclear export of nucleus accumbens-associated protein-1 (NAC1) as a novel mechanism involved in ovarian cancer resistance to taxanes, the chemotherapeutic drugs commonly used in treatment of this malignancy. We showed that NAC1, a nuclear factor of the BTB/POZ gene family, has a nuclear export signal (NES) at the N terminus (aa 17-28), and this NES critically contributes to the NAC1 nuclear-cytoplasmic shuttling when tumor cells were treated with docetaxel. Mechanistically, the nuclear-exported NAC1 bound to cullin3 (Cul3) and Cyclin B1 via its BTB and BOZ domains respectively, and the cyto-NAC1-Cul3 E3 ubiquitin ligase complex promotes the ubiquitination and degradation of Cyclin B1, thereby facilitating mitotic exit and leading to cellular resistance to docetaxel. We also showed in in vitro and in vivo experiments that TP-CH-1178, a membrane-permeable polypeptide against the NAC1 NES motif, blocked the nuclear export of NAC1, interfered with the degradation of Cyclin B1 and sensitized ovarian cancer cells to docetaxel. This study not only reveals a novel mechanism by which the NAC1 nuclear export is regulated and Cyclin B1 degradation and mitotic exit are impacted by the NAC1-Cul3 complex, but also provides the nuclear-export pathway of NAC1 as a potential target for modulating taxanes resistance in ovarian cancer and other malignancies.
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12
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Li C, Boutet A, Pascariu CM, Nelson T, Courcelles M, Wu Z, Comtois-Marotte S, Emery G, Thibault P. SUMO Proteomics Analyses Identify Protein Inhibitor of Activated STAT-Mediated Regulatory Networks Involved in Cell Cycle and Cell Proliferation. J Proteome Res 2023; 22:812-825. [PMID: 36723483 PMCID: PMC9990128 DOI: 10.1021/acs.jproteome.2c00557] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
Protein inhibitor of activated STAT (PIAS) proteins are E3 SUMO ligases playing important roles in protein stability and signaling transduction pathways. PIAS proteins are overexpressed in the triple-negative breast cancer cell line MDA-MB-231, and PIAS knockout (KO) results in a reduction in cell proliferation and cell arrest in the S phase. However, the molecular mechanisms underlying PIAS functions in cell proliferation and cell cycle remain largely unknown. Here, we used quantitative SUMO proteomics to explore the regulatory role of PIAS SUMO E3 ligases upon CRISPR/Cas9 KO of individual PIAS. A total of 1422 sites were identified, and around 10% of SUMO sites were regulated following KO of one or more PIAS genes. We identified protein substrates that were either specific to individual PIAS ligase or regulated by several PIAS ligases. Ki-67 and TOP2A, which are involved in cell proliferation and epithelial-to-mesenchymal transition, are SUMOylated at several lysine residues by all PIAS ligases, suggesting a level of redundancy between these proteins. Confocal microscopy and biochemical experiments revealed that SUMOylation regulated TOP2A protein stability, while this modification is involved in the recruitment of Ki-67 nucleolar proteins containing the SUMO interacting motif. These results provide novel insights into both the redundant and specific regulatory mechanisms of cell proliferation and cell cycle mediated by PIAS SUMO E3 ligases.
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Affiliation(s)
- Chongyang Li
- Institute for Research in Immunology and Cancer, Université de Montréal, Montréal, Québec H3T 1J4, Canada
| | - Alison Boutet
- Institute for Research in Immunology and Cancer, Université de Montréal, Montréal, Québec H3T 1J4, Canada.,Molecular Biology program, Université de Montréal, Montréal, Québec H3C 3J7, Canada
| | - Cristina Mirela Pascariu
- Institute for Research in Immunology and Cancer, Université de Montréal, Montréal, Québec H3T 1J4, Canada
| | - Trent Nelson
- Institute for Research in Immunology and Cancer, Université de Montréal, Montréal, Québec H3T 1J4, Canada.,Molecular Biology program, Université de Montréal, Montréal, Québec H3C 3J7, Canada
| | - Mathieu Courcelles
- Institute for Research in Immunology and Cancer, Université de Montréal, Montréal, Québec H3T 1J4, Canada
| | - Zhaoguan Wu
- Institute for Research in Immunology and Cancer, Université de Montréal, Montréal, Québec H3T 1J4, Canada.,Department of Chemistry, Université de Montréal, Montréal, Québec H3C 3J7, Canada
| | - Simon Comtois-Marotte
- Institute for Research in Immunology and Cancer, Université de Montréal, Montréal, Québec H3T 1J4, Canada
| | - Gregory Emery
- Institute for Research in Immunology and Cancer, Université de Montréal, Montréal, Québec H3T 1J4, Canada.,Department of Pathology and Cell Biology, Université de Montréal, Montréal, Québec H3C 3J7, Canada
| | - Pierre Thibault
- Institute for Research in Immunology and Cancer, Université de Montréal, Montréal, Québec H3T 1J4, Canada.,Molecular Biology program, Université de Montréal, Montréal, Québec H3C 3J7, Canada.,Department of Biochemistry and Molecular Medicine, Université de Montréal, Montréal, Québec H3C 3J7, Canada
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13
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Wen D, Hu M, Guo W, Wu J, Wu Y. Multi-SUMOylation of NAC1 is essential for the growth of prostate cancer cells. Biochem Biophys Res Commun 2023; 641:148-154. [PMID: 36527749 DOI: 10.1016/j.bbrc.2022.12.015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2022] [Revised: 11/21/2022] [Accepted: 12/03/2022] [Indexed: 12/14/2022]
Abstract
Nucleus accumbens-associated 1 (NAC1) is a member of pox virus and zinc finger/bric-a-brac tramtrack broad complex (BTB/POZ) gene family. Overexpression of NAC1 is implicated in cancer development, recurrence and chemotherapy resistance. In our previous study, we found NAC1 was a potential small ubiquitin-like modifier (SUMO) substrate in prostate cancer cells. However, there was still lack of evidences to further support and validate the result. In this work, we found that NAC1 is a multi-SUMO-sites acceptor. The SUMO acceptor lysines were K167, K318, K368, K483 and K498. SUMOylation didn't alter the localization of NAC1, but facilitated the formation of NAC1 nuclear bodies. Compared with NAC1 wild type (NAC1 WT), the SUMO-sites mutant of NAC1 (NAC1 SM) suppressed cell proliferation and tumor growth in cellular and animal levels. This work uncovered the function of SUMOylation of NAC1 in prostate cancer cells.
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Affiliation(s)
- Donghua Wen
- Department of Laboratory Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200123, China.
| | - Min Hu
- Department of Laboratory Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200123, China
| | - Wenzheng Guo
- Department of Laboratory Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200123, China
| | - Jingjing Wu
- Department of Laboratory Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200123, China
| | - Yingli Wu
- Hongqiao International Institute of Medicine, Shanghai Tongren Hospital / Faculty of Basic Medicine, Key Laboratory of Cell Differentiation and Apoptosis of the Chinese Ministry of Education, Chinese Academy of Medical Sciences Research Unit 2019RU043, Shanghai Jiao Tong University School of Medicine (SJTU-SM), Shanghai, 200025, China.
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14
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Shen ZH, Luo WW, Ren XC, Wang XY, Yang JM. Expression of nucleus accumbens-1 in colon cancer negatively modulates antitumor immunity. World J Gastrointest Oncol 2022; 14:2329-2339. [PMID: 36568940 PMCID: PMC9782620 DOI: 10.4251/wjgo.v14.i12.2329] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/10/2022] [Revised: 10/16/2022] [Accepted: 11/22/2022] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Nucleus accumbens-1 (NAC-1) is highly expressed in a variety of tumors, including colon cancer, and is closely associated with tumor recurrence, metastasis, and invasion.
AIM To determine whether and how NAC-1 affects antitumor immunity in colon cancer.
METHODS NAC-1-siRNA was transfected into RKO colon cancer cells to knock down NAC expression; tumor cells with or without knockdown of NAC-1 were treated with CD8+ T cells to test their cytocidal effect. The level of the immune checkpoint programmed death receptor-1 ligand (PD-L1) in colon cancer cells with or without knockdown of NAC-1 was analyzed using Quantitative real-time polymerase chain reaction and Western blotting. A double luciferase reporter assay was used to examine the effects of NAC-1 on the transcription of PD-L1. Mice bearing MC-38-OVA colon cancer cells expressing NAC-shRNA or control-shRNA were treated with OT-I mouse CD8+ T cells to determine the tumor response to immunotherapy. Immune cells in the tumor tissues were analyzed using flow cytometry. NAC-1, PD-L1 and CD8+ T cells in colon cancer specimens from patients were examined using immunohistochemistry staining.
RESULTS Knockdown of NAC-1 expression in colon cancer cells significantly enhanced the cytocidal effect of CD8+ T cells in cell culture experiments. The sensitizing effect of NAC-1 knockdown on the antitumor action of cytotoxic CD8+ T cells was recapitulated in a colon cancer xenograft animal model. Furthermore, knockdown of NAC-1 in colon cancer cells decreased the expression of PD-L1 at both the mRNA and protein levels, and this effect could be rescued by transfection of an RNAi-resistant NAC-1 expression plasmid. In a reporter gene assay, transient expression of NAC-1 in colon cancer cells increased the promoter activity of PD-L1, indicating that NAC-1 regulates PD-L1 expression at the transcriptional level. In addition, depletion of tumoral NAC-1 increased the number of CD8+ T cells but decreased the number of suppressive myeloid-derived suppressor cells and regulatory T cells.
CONCLUSION Tumor expression of NAC-1 is a negative determinant of immunotherapy.
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Affiliation(s)
- Zhao-Hua Shen
- Department of Gastroenterology, Third Xiangya Hospital, Central South University, Changsha 410013, Hunan Province, China
| | - Wei-Wei Luo
- Department of Gastroenterology, Third Xiangya Hospital, Central South University, Changsha 410013, Hunan Province, China
| | - Xing-Cong Ren
- Department of Cancer Biology and Toxicology, University of Kentucky College of Medicine, Lexington, MA 40506, United States
| | - Xiao-Yan Wang
- Department of Gastroenterology, Third Xiangya Hospital, Central South University, Changsha 410013, Hunan Province, China
| | - Jin-Ming Yang
- Department of Cancer Biology and Toxicology, University of Kentucky College of Medicine, Lexington, MA 40506, United States
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15
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Ren Y, Kumar A, Das JK, Peng HY, Wang L, Balllard D, Xiong X, Ren X, Zhang Y, Yang JM, Song J. Tumorous expression of NAC1 restrains antitumor immunity through the LDHA-mediated immune evasion. J Immunother Cancer 2022; 10:e004856. [PMID: 36150745 PMCID: PMC9511653 DOI: 10.1136/jitc-2022-004856] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/06/2022] [Indexed: 11/12/2022] Open
Abstract
BACKGROUND T cell-mediated antitumor immunity has a vital role in cancer prevention and treatment; however, the immune-suppressive tumor microenvironment (TME) constitutes a significant contributor to immune evasion that weakens antitumor immunity. Here, we explore the relationship between nucleus accumbens-associated protein-1 (NAC1), a nuclear factor of the BTB (broad-complex, Tramtrack, bric a brac)/POZ (Poxvirus, and Zinc finger) gene family, and the TME. METHODS Adoptive cell transfer (ACT) of mouse or human tumor antigen (Ag)-specific CD8+ cytotoxic T lymphocytes (CTLs) was tested in an immunocompetent or immunodeficient mouse model of melanoma with or without expression of NAC1. The effects of NAC1 expression on immune evasion in tumor cells were assessed in vitro and in vivo. CRISPR/Cas9, glycolysis analysis, retroviral transduction, quantitative real-time PCR, flow cytometric analysis, immunoblotting, database analyses were used to screen the downstream target and underlying mechanism of NAC1 in tumor cells. RESULTS Tumorous expression of NAC1 negatively impacts the CTL-mediated antitumor immunity via lactate dehydrogenase A (LDHA)-mediated suppressive TME. NAC1 positively regulated the expression of LDHA at the transcriptional level, which led to higher accumulation of lactic acid in the TME. This inhibited the cytokine production and induced exhaustion and apoptosis of CTLs, impairing their cell-killing ability. In the immunocompetent and immunodeficient mice, NAC1 depleted melanoma tumors grew significantly slower and had an elevated infiltration of tumor Ag-specific CTLs following ACT, compared with the control groups. CONCLUSIONS Tumor expression of NAC1 contributes substantially to immune evasion through its regulatory role in LDHA expression and lactic acid production. Thus, therapeutic targeting of NAC1 warrants further exploration as a potential strategy to reinforce cancer immunotherapy, such as the ACT of CTLs.
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Affiliation(s)
- Yijie Ren
- Microbial Pathogenesis and Immunology, Texas A&M University Health Sciences Center, Bryan, Texas, USA
| | - Anil Kumar
- Microbial Pathogenesis and Immunology, Texas A&M University Health Sciences Center, Bryan, Texas, USA
| | - Jugal K Das
- Microbial Pathogenesis and Immunology, Texas A&M University Health Sciences Center, Bryan, Texas, USA
| | - Hao-Yun Peng
- Microbial Pathogenesis and Immunology, Texas A&M University Health Sciences Center, Bryan, Texas, USA
| | - Liqing Wang
- Microbial Pathogenesis and Immunology, Texas A&M University Health Sciences Center, Bryan, Texas, USA
| | - Darby Balllard
- Microbial Pathogenesis and Immunology, Texas A&M University Health Sciences Center, Bryan, Texas, USA
| | - Xiaofang Xiong
- Microbial Pathogenesis and Immunology, Texas A&M University Health Sciences Center, Bryan, Texas, USA
| | - Xingcong Ren
- Toxicology and Cancer Biology, University of Kentucky, Lexington, Kentucky, USA
| | - Yi Zhang
- Toxicology and Cancer Biology, University of Kentucky, Lexington, Kentucky, USA
| | - Jin-Ming Yang
- Toxicology and Cancer Biology, University of Kentucky, Lexington, Kentucky, USA
| | - Jianxun Song
- Microbial Pathogenesis and Immunology, Texas A&M University Health Sciences Center, Bryan, Texas, USA
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16
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Yang JM, Ren Y, Kumar A, Xiong X, Das JK, Peng HY, Wang L, Ren X, Zhang Y, Ji C, Cheng Y, Zhang L, Alaniz RC, de Figueiredo P, Fang D, Zhou H, Liu X, Wang J, Song J. NAC1 modulates autoimmunity by suppressing regulatory T cell-mediated tolerance. SCIENCE ADVANCES 2022; 8:eabo0183. [PMID: 35767626 PMCID: PMC9242588 DOI: 10.1126/sciadv.abo0183] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/07/2022] [Accepted: 05/12/2022] [Indexed: 05/28/2023]
Abstract
We report here that nucleus accumbens-associated protein-1 (NAC1), a nuclear factor of the Broad-complex, Tramtrack, Bric-a-brac/poxvirus and zinc finger (BTB/POZ) gene family, is a negative regulator of FoxP3 in regulatory T cells (Tregs) and a critical determinant of immune tolerance. Phenotypically, NAC1-/- mice showed substantial tolerance to the induction of autoimmunity and generated a larger amount of CD4+ Tregs that exhibit a higher metabolic profile and immune-suppressive activity, increased acetylation and expression of FoxP3, and slower turnover of this transcription factor. Treatment of Tregs with the proinflammatory cytokines interleukin-1β or tumor necrosis factor-α induced a robust up-regulation of NAC1 but evident down-regulation of FoxP3 as well as the acetylated FoxP3. These findings imply that NAC1 acts as a trigger of the immune response through destabilization of Tregs and suppression of tolerance induction, and targeting of NAC1 warrants further exploration as a potential tolerogenic strategy for treatment of autoimmune disorders.
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Affiliation(s)
- Jin-Ming Yang
- Department of Toxicology and Cancer Biology, Department of Pharmacology and Nutritional Science, and Markey Cancer Center, University of Kentucky College of Medicine, Lexington, KY 40536, USA
| | - Yijie Ren
- Department of Microbial Pathogenesis and Immunology, Texas A&M University Health Science Center, Bryan, TX 77807, USA
| | - Anil Kumar
- Department of Microbial Pathogenesis and Immunology, Texas A&M University Health Science Center, Bryan, TX 77807, USA
| | - Xiaofang Xiong
- Department of Microbial Pathogenesis and Immunology, Texas A&M University Health Science Center, Bryan, TX 77807, USA
| | - Jugal Kishore Das
- Department of Microbial Pathogenesis and Immunology, Texas A&M University Health Science Center, Bryan, TX 77807, USA
| | - Hao-Yun Peng
- Department of Microbial Pathogenesis and Immunology, Texas A&M University Health Science Center, Bryan, TX 77807, USA
| | - Liqing Wang
- Department of Microbial Pathogenesis and Immunology, Texas A&M University Health Science Center, Bryan, TX 77807, USA
| | - Xingcong Ren
- Department of Toxicology and Cancer Biology, Department of Pharmacology and Nutritional Science, and Markey Cancer Center, University of Kentucky College of Medicine, Lexington, KY 40536, USA
| | - Yi Zhang
- Department of Toxicology and Cancer Biology, Department of Pharmacology and Nutritional Science, and Markey Cancer Center, University of Kentucky College of Medicine, Lexington, KY 40536, USA
| | - Cheng Ji
- Department of Toxicology and Cancer Biology, Department of Pharmacology and Nutritional Science, and Markey Cancer Center, University of Kentucky College of Medicine, Lexington, KY 40536, USA
| | - Yan Cheng
- Department of Toxicology and Cancer Biology, Department of Pharmacology and Nutritional Science, and Markey Cancer Center, University of Kentucky College of Medicine, Lexington, KY 40536, USA
| | - Li Zhang
- Department of Toxicology and Cancer Biology, Department of Pharmacology and Nutritional Science, and Markey Cancer Center, University of Kentucky College of Medicine, Lexington, KY 40536, USA
| | - Robert C. Alaniz
- Department of Microbial Pathogenesis and Immunology, Texas A&M University Health Science Center, Bryan, TX 77807, USA
| | - Paul de Figueiredo
- Department of Microbial Pathogenesis and Immunology, Texas A&M University Health Science Center, Bryan, TX 77807, USA
- Department of Veterinary Pathobiology, Texas A&M University, College Station, TX 77845, USA
- Norman Borlaug Center, Texas A&M University, College Station, TX 77845, USA
| | - Deyu Fang
- Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
| | - Hongwei Zhou
- Department of Medicine, Columbia Center for Human Development, Columbia University Irving Medical Center, New York, NY 10032, USA
| | - Xiaoqi Liu
- Department of Toxicology and Cancer Biology, Department of Pharmacology and Nutritional Science, and Markey Cancer Center, University of Kentucky College of Medicine, Lexington, KY 40536, USA
| | - Jianlong Wang
- Department of Medicine, Columbia Center for Human Development, Columbia University Irving Medical Center, New York, NY 10032, USA
| | - Jianxun Song
- Department of Microbial Pathogenesis and Immunology, Texas A&M University Health Science Center, Bryan, TX 77807, USA
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17
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Antonescu CR, Dickson BC, Zhang L, Sung YS, Fletcher CD. Unclassified low grade spindle cell sarcoma with storiform pattern characterized by recurrent novel EWSR1/FUS-NACC1 fusions. Mod Pathol 2021; 34:1541-1546. [PMID: 33859361 PMCID: PMC8298288 DOI: 10.1038/s41379-021-00805-x] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2021] [Revised: 03/10/2021] [Accepted: 03/12/2021] [Indexed: 12/17/2022]
Abstract
Despite extraordinary advances in the molecular characterization of soft tissue tumors as a result of the widespread application of next generation sequencing in clinical practice, a subset of lesions remain difficult to diagnose. In this study we describe 3 unclassified spindle cell sarcomas with a monomorphic cytomorphology and distinctive storiform growth, characterized by novel fusions between EWSR1 or FUS1, and NACC1 genes. The tumors occurred in 3 young adult females (age range: 29-31) involving deep soft tissues, two located in the lower extremity and one in the abdominal wall. All three tumors showed patchy positivity for S100 protein, while being negative for SOX10 and retained H3K27me3 expression. All cases were negative for epithelial or muscle markers. As the findings were non-specific, molecular studies using targeted panels of RNA sequencing were performed, including one case tested by TruSight RNA Fusion Panel and 2 cases by Archer FusionPlex. The results showed 2 cases were positive for FUS-NACC1 and one for EWSR1-NACC1 fusions. These findings were further confirmed by FISH using custom BAC probes for a dual-color fusion assay. These results suggest the possibility of a previously undescribed soft tissue neoplasm characterized by a uniform spindle cell phenotype arranged in a storiform and fascicular pattern, expressing S100 protein and harboring NACC1-related fusions. The biologic behavior of this tumor remains to be determined.
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Affiliation(s)
| | - Brendan C. Dickson
- Department of Pathology & Laboratory Medicine, Mount Sinai Hospital, Toronto, ON, Canada
| | - Lei Zhang
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Yun-Shao Sung
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
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Mehravar M, Ghaemimanesh F, Poursani EM. An Overview on the Complexity of OCT4: at the Level of DNA, RNA and Protein. Stem Cell Rev Rep 2021; 17:1121-1136. [PMID: 33389631 DOI: 10.1007/s12015-020-10098-3] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/25/2020] [Indexed: 10/22/2022]
Abstract
OCT4 plays critical roles in self-renewal and pluripotency maintenance of embryonic stem cells, and is considered as one of the main stemness markers. It also has pivotal roles in early stages of embryonic development. Most studies on OCT4 have focused on the expression and function of OCT4A, which is the biggest isoform of OCT4 known so far. Recently, many studies have shown that OCT4 has various transcript variants, protein isoforms, as well as pseudogenes. Distinguishing the expression and function of these variants and isoforms is a big challenge in expression profiling studies of OCT4. Understanding how OCT4 is functioning in different contexts, depends on knowing of where and when each of OCT4 transcripts, isoforms and pseudogenes are expressed. Here, we review OCT4 known transcripts, isoforms and pseudogenes, as well as its interactions with other proteins, and emphasize the importance of discriminating each of them in order to understand the exact function of OCT4 in stem cells, normal development and development of diseases.
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Affiliation(s)
- Majid Mehravar
- Department of Anatomy and Developmental Biology, Development and Stem Cells Program, Biomedicine Discovery Institute, Monash University, Melbourne, Australia
| | - Fatemeh Ghaemimanesh
- Monoclonal Antibody Research Center, Avicenna Research Institute, ACECR, Tehran, Iran
| | - Ensieh M Poursani
- Hematology, Oncology and Stem Cell Transplantation Research Center, Tehran University of Medical Sciences, Tehran, Iran.
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Lyu B, Dong Y, Kang J. A New Case of de novo Variant c.892C>T (p.Arg298Trp) in NACC1: A First Case Report From China. Front Pediatr 2021; 9:754261. [PMID: 34869110 PMCID: PMC8634650 DOI: 10.3389/fped.2021.754261] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/06/2021] [Accepted: 10/04/2021] [Indexed: 11/13/2022] Open
Abstract
Background: The nucleus accumbens associated 1 (NACC1) gene is a transcription factor member of the BTB/POZ family. A de novo heterozygous c.892C>T (p.Arg298Trp) variant in the NACC1 may define a syndrome characterized by intellectual disability, infantile epilepsy, congenital cataract, and feeding difficulties. Case Presentation: We report a new case with a neurodevelopmental disorder characterized by severe intellectual disability, infantile epilepsy, congenital cataract, and feeding difficulties. Brain MRI reveals brain dysplasia. We observe a de novo heterozygous c.892C>T (p.Arg298Trp) variant in the NACC1 gene in this case. Now, the child regularly goes to the hospital for rehabilitation training (once a month). Sodium Valproate (10 mg/kg/day) and Clobazam (10 mg/kg/day) are used in the treatment of epilepsy. A total of three articles were screened, and two papers were excluded. The search revealed one article related to a syndrome caused by a de novo heterozygous c.892C>T (p.Arg298Trp) variant in the NACC1; they screened the main clinical features of eight cases of a syndrome, which were summarized and analyzed. Conclusions: The NACC1 gene is a member of the BTB/POZ family of transcription factors. A de novo heterozygous c.892C>T (p.Arg298Trp) variant in the NACC1 may define a syndrome characterized by intellectual disability, infantile epilepsy, congenital cataract, and feeding difficulties. At present, there is no effective cure. In the future, we need more cases to determine the phenotype-genotype correlation of NACC1 variants. Many questions remain to be answered, and many challenges remain to be faced. Future transcriptional studies may further clarify this rare, recurrent variant, and could potentially lead to targeted therapies.
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Affiliation(s)
- Baiyu Lyu
- Department of Pediatrics, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Yan Dong
- Department of Pediatrics, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Juan Kang
- Department of Pediatrics, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
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Nucleus Accumbens-Associated Protein 1 Binds DNA Directly through the BEN Domain in a Sequence-Specific Manner. Biomedicines 2020; 8:biomedicines8120608. [PMID: 33327466 PMCID: PMC7764960 DOI: 10.3390/biomedicines8120608] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2020] [Revised: 12/10/2020] [Accepted: 12/10/2020] [Indexed: 01/03/2023] Open
Abstract
Nucleus accumbens-associated protein 1 (NAC1) is a nuclear protein that harbors an amino-terminal BTB domain and a carboxyl-terminal BEN domain. NAC1 appears to play significant and diverse functions in cancer and stem cell biology. Here we demonstrated that the BEN domain of NAC1 is a sequence-specific DNA-binding domain. We selected the palindromic 6 bp motif ACATGT as a target sequence by using a PCR-assisted random oligonucleotide selection approach. The interaction between NAC1 and target DNA was characterized by gel shift assays, pull-down assays, isothermal titration calorimetry (ITC), chromatin-immunoprecipitation assays, and NMR chemical shifts perturbation (CSP). The solution NMR structure revealed that the BEN domain of human NAC-1 is composed of five conserved α helices and two short β sheets, with an additional hitherto unknown N-terminal α helix. In particular, ITC clarified that there are two sequential events in the titration of the BEN domain of NAC1 into the target DNA. The ITC results were further supported by CSP data and structure analyses. Furthermore, live cell photobleaching analyses revealed that the BEN domain of NAC1 alone was unable to interact with chromatin/other proteins in cells.
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Wang H, Wang X, Zhang Y, Cheng R, Yuan J, Zhong Z. Systemic Delivery of NAC-1 siRNA by Neuropilin-Targeted Polymersomes Sensitizes Antiangiogenic Therapy of Metastatic Triple-Negative Breast Cancer. Biomacromolecules 2020; 21:5119-5127. [PMID: 33174734 DOI: 10.1021/acs.biomac.0c01253] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Antiangiogenic therapy with bevacizumab while being interesting for metastatic triple-negative breast cancer (mTNBC) is restrained by tumor hypoxia elevation and cancer stem cell enrichment. Here, we find that neuropilin-1 (NRP-1)-targeted delivery of nucleus accumbens-associated protein-1 (NAC-1) siRNA mediated by tLyP-1 peptide-functionalized chimaeric polymersomes (tLyP-1-Ps) effectively sensitizes antiangiogenic therapy of mTNBC in vivo. tLyP-1-Ps showed good encapsulation (up to 14.4 wt. %) of siNAC-1, giving robust tLyP-1-Ps-siNAC-1 nanoformulation with a defined size of 48.5 nm (PDI = 0.13) and a surface charge of -9.2 mV, and mediated efficient cytoplasmic transportation of siNAC-1 in MDA-MB-231 TNBC cells, resulting in significant silencing of NAC-1 mRNA and the corresponding oncoprotein. Transwell invasion and wound healing assays revealed that tLyP-1-Ps-siNAC-1 potently inhibited MDA-MB-231 cell invasion and migration. Intriguingly, tLyP-1-Ps-siNAC-1 was shown to markedly improve the bevacizumab therapy of mTNBC, significantly curbing lung metastasis and prolonging the survival time of the MDA-MB-231 metastatic model. The combination of targeted NAC-1 gene silencing and antiangiogenic therapy appears to be an innovative treatment for mTNBC.
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Affiliation(s)
- Hongyu Wang
- Biomedical Polymers Laboratory, College of Chemistry, Chemical Engineering and Materials Science, and State Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou 215123, P. R. China
| | - Xiaohui Wang
- Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, P. R. China
| | - Yi Zhang
- Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, P. R. China
| | - Ru Cheng
- Biomedical Polymers Laboratory, College of Chemistry, Chemical Engineering and Materials Science, and State Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou 215123, P. R. China
| | - Jiandong Yuan
- BrightGene Bio-Medical Technology Company, Ltd., Suzhou 215123, P. R. China
| | - Zhiyuan Zhong
- Biomedical Polymers Laboratory, College of Chemistry, Chemical Engineering and Materials Science, and State Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou 215123, P. R. China
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22
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Downregulation of the ubiquitin ligase KBTBD8 prevented epithelial ovarian cancer progression. Mol Med 2020; 26:96. [PMID: 33109073 PMCID: PMC7590797 DOI: 10.1186/s10020-020-00226-7] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2019] [Accepted: 10/12/2020] [Indexed: 12/24/2022] Open
Abstract
OBJECTIVES Kelch repeat and BTB domain-containing protein 8, KBTBD8, has been identified as a female fertility factor. However, there have been no reports on the role of KBTBD8 in the progression of epithelial ovarian cancer, EOC. Our study aimed to address this issue. METHODS We first examine KBTBD8 expression in EOC tissues and cells. Next, we performed RNA sequencing to reveal the overall mechanism. Then we investigated the roles of KBTBD8 in the proliferation, migration, and health status of cultured EOC cells. Finally, we employed tumor xenograft models to evaluate the role of KBTBD8 in vivo. RESULTS First, KBTBD8 level was significantly higher in EOC tissues and cells. Next, comparative RNA sequencing identified more tumorigenesis-related genes that KBTBD8 might regulate. Then we found that KBTBD8 knockdown significantly decreased EOC cell proliferation, migration, and the activities of multiple tumorigenesis-related kinases. Finally, KBTBD8 knockdown significantly diminished ovarian tumor formation in vivo. CONCLUSION Proper KBTBD8 level is essential for the healthy growth of ovarian somatic cells, such as ovarian epithelial cells. Excessive KBTBD8 might be a significant impetus for EOC progression. KBTBD8 reduction greatly inhibits EOC proliferation and migration.
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Li L, Yu H, Ren Q. MiR-218-5p Suppresses the Progression of Retinoblastoma Through Targeting NACC1 and Inhibiting the AKT/mTOR Signaling Pathway. Cancer Manag Res 2020; 12:6959-6967. [PMID: 32821163 PMCID: PMC7418178 DOI: 10.2147/cmar.s246142] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2020] [Accepted: 06/17/2020] [Indexed: 12/23/2022] Open
Abstract
Introduction MicroRNA-218-5p (miR-218-5p) was involved in the progression of multiple tumors as a tumor suppressor miRNA. Its specific role on human retinoblastoma (RB) cells remains unknown. Methods We constructed the miR-218-5p overexpression and knockdown cells to detect their role on RB cell line WERI-Rb-1, and we analyzed its binding sites on TargetScan. CCK8 and clonogenic assays were performed to detect cell viability. Flow cytometry was used for the detection of cell apoptosis. Results Our results showed that the miR-218-5p inhibitor enhanced cell viability and blocked the apoptosis in RB cells. The AKT/mTOR signaling pathway was also inhibited by the miR-218-5p inhibitor. MiR-218-5p mimics lead to diametrically opposite results. Nucleus accumbens-associated 1 (NAC1) encoded by the NACC1 gene is involved in the regulation of many biological functions, including gene transcription, protein degradation of ubiquitin pathway, cell viability, and apoptosis. In this research, dataset analysis suggested that NACC1 might be a downstream target of miR-218-5p. Then, qPCR and Western blot analysis proved that miR-218-5p inhibited the expression of NACC1 in RB cells. NACC1 could promote cell viability and inhibit the apoptosis by activating the AKT/mTOR signaling pathway. MiR-218-5p mimics blocked the enhancement of cell growth induced by NACC1 overexpression as well as the activation of the AKT/mTOR signaling pathway in RB cells. Discussion MiR-218-5p inhibited cell growth by targeting NACC1 and suppressing the AKT/mTOR signaling pathway. MiR-218-5p/NACC1/AKT/mTOR might be a new target axis for the clinical treatment strategy.
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Affiliation(s)
- Li Li
- Department of Ophthalmology, The First Hospital of Shijiazhuang, Shijiazhuang, Hebei, People's Republic of China
| | - Hua Yu
- Department of Ophthalmology, The First Hospital of Shijiazhuang, Shijiazhuang, Hebei, People's Republic of China
| | - Qian Ren
- Department of Ophthalmology, The First Hospital of Shijiazhuang, Shijiazhuang, Hebei, People's Republic of China
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Pan X, Lu L, Cai YD. Predicting protein subcellular location with network embedding and enrichment features. BIOCHIMICA ET BIOPHYSICA ACTA-PROTEINS AND PROTEOMICS 2020; 1868:140477. [PMID: 32593761 DOI: 10.1016/j.bbapap.2020.140477] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/31/2020] [Revised: 06/17/2020] [Accepted: 06/22/2020] [Indexed: 02/06/2023]
Abstract
The subcellular location of a protein is highly related to its function. Identifying the location of a given protein is an essential step for investigating its related problems. Traditional experimental methods can produce solid determination. However, their limitations, such as high cost and low efficiency, are evident. Computational methods provide an alternative means to address these problems. Most previous methods constantly extract features from protein sequences or structures for building prediction models. In this study, we use two types of features and combine them to construct the model. The first feature type is extracted from a protein-protein interaction network to abstract the relationship between the encoded protein and other proteins. The second type is obtained from gene ontology and biological pathways to indicate the existing functions of the encoded protein. These features are analyzed using some feature selection methods. The final optimum features are adopted to build the model with recurrent neural network as the classification algorithm. Such model yields good performance with Matthews correlation coefficient of 0.844. A decision tree is used as a rule learning classifier to extract decision rules. Although the performance of decision rules is poor, they are valuable in revealing the molecular mechanism of proteins with different subcellular locations. The final analysis confirms the reliability of the extracted rules. The source code of the propose method is freely available at https://github.com/xypan1232/rnnloc.
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Affiliation(s)
- Xiaoyong Pan
- School of Life Sciences, Shanghai University, Shanghai 200444, People's Republic of China; Institute of Image Processing and Pattern Recognition, Shanghai Jiao Tong University, Key Laboratory of System Control and Information Processing, Ministry of Education of China, 200240 Shanghai, China
| | - Lin Lu
- Department of Radiology, Columbia University Medical Center, NewYork, NY, 10032, USA.
| | - Yu-Dong Cai
- School of Life Sciences, Shanghai University, Shanghai 200444, People's Republic of China.
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25
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Sanchez A, Kuras M, Murillo JR, Pla I, Pawlowski K, Szasz AM, Gil J, Nogueira FCS, Perez-Riverol Y, Eriksson J, Appelqvist R, Miliotis T, Kim Y, Baldetorp B, Ingvar C, Olsson H, Lundgren L, Ekedahl H, Horvatovich P, Sugihara Y, Welinder C, Wieslander E, Kwon HJ, Domont GB, Malm J, Rezeli M, Betancourt LH, Marko-Varga G. Novel functional proteins coded by the human genome discovered in metastases of melanoma patients. Cell Biol Toxicol 2020; 36:261-272. [PMID: 31599373 PMCID: PMC7320927 DOI: 10.1007/s10565-019-09494-4] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2019] [Accepted: 09/02/2019] [Indexed: 12/18/2022]
Abstract
In the advanced stages, malignant melanoma (MM) has a very poor prognosis. Due to tremendous efforts in cancer research over the last 10 years, and the introduction of novel therapies such as targeted therapies and immunomodulators, the rather dark horizon of the median survival has dramatically changed from under 1 year to several years. With the advent of proteomics, deep-mining studies can reach low-abundant expression levels. The complexity of the proteome, however, still surpasses the dynamic range capabilities of current analytical techniques. Consequently, many predicted protein products with potential biological functions have not yet been verified in experimental proteomic data. This category of 'missing proteins' (MP) is comprised of all proteins that have been predicted but are currently unverified. As part of the initiative launched in 2016 in the USA, the European Cancer Moonshot Center has performed numerous deep proteomics analyses on samples from MM patients. In this study, nine MPs were clearly identified by mass spectrometry in MM metastases. Some MPs significantly correlated with proteins that possess identical PFAM structural domains; and other MPs were significantly associated with cancer-related proteins. This is the first study to our knowledge, where unknown and novel proteins have been annotated in metastatic melanoma tumour tissue.
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Affiliation(s)
- Aniel Sanchez
- Section for Clinical Chemistry, Department of Translational Medicine, Skåne University Hospital Malmö, Lund University, 205 02, Malmö, Sweden.
| | - Magdalena Kuras
- Clinical Protein Science & Imaging, Biomedical Centre, Department of Biomedical Engineering, Lund University, BMC D13, 221 84, Lund, Sweden
| | - Jimmy Rodriguez Murillo
- Clinical Protein Science & Imaging, Biomedical Centre, Department of Biomedical Engineering, Lund University, BMC D13, 221 84, Lund, Sweden
| | - Indira Pla
- Section for Clinical Chemistry, Department of Translational Medicine, Skåne University Hospital Malmö, Lund University, 205 02, Malmö, Sweden
| | - Krzysztof Pawlowski
- Section for Clinical Chemistry, Department of Translational Medicine, Skåne University Hospital Malmö, Lund University, 205 02, Malmö, Sweden
- Biology, Warsaw University of Life Sciences, Warsaw, Poland
| | - A Marcell Szasz
- Cancer Center, Semmelweis University, Budapest, 1083, Hungary
| | - Jeovanis Gil
- Clinical Protein Science & Imaging, Biomedical Centre, Department of Biomedical Engineering, Lund University, BMC D13, 221 84, Lund, Sweden
| | - Fábio C S Nogueira
- Proteomics Unit, Department of Biochemistry, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
- Laboratory of Proteomics, LADETEC, Institute of Chemistry, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Yasset Perez-Riverol
- European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Trust Genome Campus, CB10 1SD Hinxton, Cambridge, UK
| | - Jonatan Eriksson
- Clinical Protein Science & Imaging, Biomedical Centre, Department of Biomedical Engineering, Lund University, BMC D13, 221 84, Lund, Sweden
| | - Roger Appelqvist
- Clinical Protein Science & Imaging, Biomedical Centre, Department of Biomedical Engineering, Lund University, BMC D13, 221 84, Lund, Sweden
| | | | - Yonghyo Kim
- Clinical Protein Science & Imaging, Biomedical Centre, Department of Biomedical Engineering, Lund University, BMC D13, 221 84, Lund, Sweden
| | - Bo Baldetorp
- Division of Oncology and Pathology, Department of Clinical Sciences Lund, Lund University, 221 85, Lund, Sweden
| | - Christian Ingvar
- Department of Surgery, Clinical Sciences, Skåne University Hospital, Lund University, Lund, Sweden
| | - Håkan Olsson
- Division of Oncology and Pathology, Department of Clinical Sciences Lund, Lund University, 221 85, Lund, Sweden
| | - Lotta Lundgren
- Division of Oncology and Pathology, Department of Clinical Sciences Lund, Lund University, 221 85, Lund, Sweden
- Department of Hematology, Oncology and Radiation Physics, Skåne University Hospital, Lund, Sweden
| | - Henrik Ekedahl
- Division of Oncology and Pathology, Department of Clinical Sciences Lund, Lund University, 221 85, Lund, Sweden
| | - Peter Horvatovich
- Department of Analytical Biochemistry, Faculty of Science and Engineering, University of Groningen, Groningen, The Netherlands
| | - Yutaka Sugihara
- Division of Oncology and Pathology, Department of Clinical Sciences Lund, Lund University, 221 85, Lund, Sweden
| | - Charlotte Welinder
- Division of Oncology and Pathology, Department of Clinical Sciences Lund, Lund University, 221 85, Lund, Sweden
| | - Elisabet Wieslander
- Division of Oncology and Pathology, Department of Clinical Sciences Lund, Lund University, 221 85, Lund, Sweden
| | - Ho Jeong Kwon
- Department of Biotechnology, Yonsei University, Seoul, South Korea
| | - Gilberto B Domont
- Proteomics Unit, Department of Biochemistry, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Johan Malm
- Section for Clinical Chemistry, Department of Translational Medicine, Skåne University Hospital Malmö, Lund University, 205 02, Malmö, Sweden
| | - Melinda Rezeli
- Clinical Protein Science & Imaging, Biomedical Centre, Department of Biomedical Engineering, Lund University, BMC D13, 221 84, Lund, Sweden
| | - Lazaro Hiram Betancourt
- Clinical Protein Science & Imaging, Biomedical Centre, Department of Biomedical Engineering, Lund University, BMC D13, 221 84, Lund, Sweden.
| | - György Marko-Varga
- Clinical Protein Science & Imaging, Biomedical Centre, Department of Biomedical Engineering, Lund University, BMC D13, 221 84, Lund, Sweden
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Gao M, Herlinger AL, Wu R, Wang TL, Shih IM, Kong B, Rangel LBA, Yang JM. NAC1 attenuates BCL6 negative autoregulation and functions as a BCL6 coactivator of FOXQ1 transcription in cancer cells. Aging (Albany NY) 2020; 12:9275-9291. [PMID: 32412910 PMCID: PMC7288929 DOI: 10.18632/aging.103203] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2019] [Accepted: 03/09/2020] [Indexed: 01/08/2023]
Abstract
Background: Nucleus accumbens-associated protein 1 (NAC1) has multifaceted roles in cancer pathogenesis and progression, including the development of drug resistance, promotion of cytokinesis, and maintenance of “stem cell-like” phenotypes. NAC1 is a transcriptional co-regulator belonging to the bric-a-brac tramtrack broad (BTB) family of proteins, although it lacks the characteristic DNA binding motif of the BTB family. The formation of higher-order transcription complexes likely depends on its interaction with other DNA-binding co-factors. Results: NAC1 interacts with BCL6 via its C-terminal BEN domain and forms a complex that binds the promoter region and activates transcription of the NAC1 target gene, FOXQ1. NAC1 and BCL6 were coordinately upregulated. Our analysis also identified a novel function of NAC1 in attenuating BCL6 auto-downregulation in ovarian cancer. Lastly, we found a significant overlap among NAC1- and BCL6-regulated genes in tumor cells, suggesting that NAC1 and BCL6 coordinately control transcription in cancer. Conclusions: The results of this study provide a novel mechanistic insight into the oncogenic roles of NAC1 and underline the importance of developing the NAC1/BCL6-targeted cancer therapy. Methods: Using the Cistrome database and Chromatin Immunoprecipitation (ChIP) analyses, we identified BCL6 as a potential NAC1- interacting molecule. Co-immunoprecipitation (Co-IP), luciferase reporter assay, immunohistochemistry and microarray analysis were performed to analyze the interaction between NAC1 and BCL6 and the mechanisms by which they regulate the downstream genes including FOXQ1.
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Affiliation(s)
- Min Gao
- Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Jinan, PR China.,Departments of Gynecology and Obstetrics, Oncology and Pathology, Johns Hopkins Medical Institutions, Baltimore, MD 21287, USA
| | - Alice Laschuk Herlinger
- Departments of Gynecology and Obstetrics, Oncology and Pathology, Johns Hopkins Medical Institutions, Baltimore, MD 21287, USA.,Biotechnology Program/Renorbio, Health Science Center, Federal University of Espírito Santo, Vitória, Brazil.,Department of Genetics, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil
| | - Renchin Wu
- Departments of Gynecology and Obstetrics, Oncology and Pathology, Johns Hopkins Medical Institutions, Baltimore, MD 21287, USA
| | - Tian-Li Wang
- Departments of Gynecology and Obstetrics, Oncology and Pathology, Johns Hopkins Medical Institutions, Baltimore, MD 21287, USA
| | - Ie-Ming Shih
- Departments of Gynecology and Obstetrics, Oncology and Pathology, Johns Hopkins Medical Institutions, Baltimore, MD 21287, USA
| | - Beihua Kong
- Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Jinan, PR China
| | - Leticia Batista Azevedo Rangel
- Biotechnology Program/Renorbio, Health Science Center, Federal University of Espírito Santo, Vitória, Brazil.,Biochemistry and Pharmacology Program, Health Science Center, Federal University of Espírito Santo, Vitória, Brazil.,Department of Pharmaceutical Sciences, Federal University of Espírito Santo, Vitória, Brazil
| | - Jin-Ming Yang
- Department of Toxicology and Cancer Biology, College of Medicine, Markey Cancer Center, University of Kentucky, Lexington, KY 40536, USA
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Đukić A, Lulić L, Thomas M, Skelin J, Bennett Saidu NE, Grce M, Banks L, Tomaić V. HPV Oncoproteins and the Ubiquitin Proteasome System: A Signature of Malignancy? Pathogens 2020; 9:pathogens9020133. [PMID: 32085533 PMCID: PMC7168213 DOI: 10.3390/pathogens9020133] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2019] [Revised: 02/10/2020] [Accepted: 02/11/2020] [Indexed: 12/22/2022] Open
Abstract
Human papillomavirus (HPV) E6 and E7 oncoproteins are critical for development and maintenance of the malignant phenotype in HPV-induced cancers. These two viral oncoproteins interfere with a plethora of cellular pathways, including the regulation of cell cycle and the control of apoptosis, which are critical in maintaining normal cellular functions. E6 and E7 bind directly with certain components of the Ubiquitin Proteasome System (UPS), enabling them to manipulate a number of important cellular pathways. These activities are the means by which HPV establishes an environment supporting the normal viral life cycle, however in some instances they can also lead to the development of malignancy. In this review, we have discussed how E6 and E7 oncoproteins from alpha and beta HPV types interact with the components of the UPS, and how this interplay contributes to the development of cancer.
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Affiliation(s)
- Anamaria Đukić
- Division of Molecular Medicine, Ruđer Bošković Institute, Bijenička cesta 54, 10000 Zagreb, Croatia; (A.Đ.); (L.L.); (J.S.); (N.E.B.S.); (M.G.)
| | - Lucija Lulić
- Division of Molecular Medicine, Ruđer Bošković Institute, Bijenička cesta 54, 10000 Zagreb, Croatia; (A.Đ.); (L.L.); (J.S.); (N.E.B.S.); (M.G.)
| | - Miranda Thomas
- International Centre for Genetic Engineering and Biotechnology, AREA Science Park, Padriciano 99, I-34149 Trieste, Italy; (M.T.); (L.B.)
| | - Josipa Skelin
- Division of Molecular Medicine, Ruđer Bošković Institute, Bijenička cesta 54, 10000 Zagreb, Croatia; (A.Đ.); (L.L.); (J.S.); (N.E.B.S.); (M.G.)
| | - Nathaniel Edward Bennett Saidu
- Division of Molecular Medicine, Ruđer Bošković Institute, Bijenička cesta 54, 10000 Zagreb, Croatia; (A.Đ.); (L.L.); (J.S.); (N.E.B.S.); (M.G.)
| | - Magdalena Grce
- Division of Molecular Medicine, Ruđer Bošković Institute, Bijenička cesta 54, 10000 Zagreb, Croatia; (A.Đ.); (L.L.); (J.S.); (N.E.B.S.); (M.G.)
| | - Lawrence Banks
- International Centre for Genetic Engineering and Biotechnology, AREA Science Park, Padriciano 99, I-34149 Trieste, Italy; (M.T.); (L.B.)
| | - Vjekoslav Tomaić
- Division of Molecular Medicine, Ruđer Bošković Institute, Bijenička cesta 54, 10000 Zagreb, Croatia; (A.Đ.); (L.L.); (J.S.); (N.E.B.S.); (M.G.)
- Correspondence: ; Tel.: +385-1-4561110; Fax: +385-1-4561010
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Tang XH, Li H, Zheng XS, Lu MS, An Y, Zhang XL. CRM197 reverses paclitaxel resistance by inhibiting the NAC-1/Gadd45 pathway in paclitaxel-resistant ovarian cancer cells. Cancer Med 2019; 8:6426-6436. [PMID: 31490008 PMCID: PMC6797568 DOI: 10.1002/cam4.2512] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2019] [Revised: 08/02/2019] [Accepted: 08/11/2019] [Indexed: 12/19/2022] Open
Abstract
Heparin‐binding epidermal growth factor‐like growth factor (HB‐EGF) is a new promising target for the treatment of ovarian cancer. Our previous study showed that cross‐reacting material 197 (CRM197), a specific HB‐EGF inhibitor, significantly reverses resistance against paclitaxel in paclitaxel‐resistant ovarian cancer cells. However, the mechanism of the effect of CRM197 on the reversion of paclitaxel resistance was unclear. In this study, in vitro and in vivo data suggested that CRM197 treatment sensitized paclitaxel‐resistant ovarian cancer cells to paclitaxel, at least in part, via nucleus accumbens‐1 (NAC‐1) and its downstream pathway, DNA damage‐inducible 45‐γ interacting protein (Gadd45gip1)/growth arrest and DNA damage‐inducible 45 (Gadd45), in A2780/Taxol and SKOV3/Taxol cells. The results also showed that CRM197 activated the proapoptotic JNK/p38MAPK pathway to enhance caspase‐3 activity and apoptosis by downregulation of the NAC‐1/Gadd45gip1/Gadd45 pathway, leading to reversion of paclitaxel resistance in A2780/Taxol and SKOV3/Taxol cells. This study provides the first mechanism through which CRM197 significantly reverses resistance against paclitaxel by modulating the NAC‐1/Gadd45gip1/Gadd45 pathway in paclitaxel‐resistant ovarian cancer cells, and the mechanism of HB‐EGF inhibition as a novel therapeutic strategy for patients with paclitaxel‐resistant ovarian cancer.
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Affiliation(s)
- Xiao-Han Tang
- Department of Gynecology and Obstetrics, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Hui Li
- Department of Gynecology and Obstetrics, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Xiu-Shuang Zheng
- Department of Gynecology and Obstetrics, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Mei-Song Lu
- Department of Gynecology and Obstetrics, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Yuan An
- Department of Gynecology and Obstetrics, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Xiao-Lei Zhang
- Department of Gynecology and Obstetrics, The First Affiliated Hospital of Harbin Medical University, Harbin, China
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29
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Xia Z, Xu G, Nie L, Liu L, Peng N, He Q, Zuo Q, Zhou Y, Cao Z, Liu S, Zhu Y. NAC1 Potentiates Cellular Antiviral Signaling by Bridging MAVS and TBK1. THE JOURNAL OF IMMUNOLOGY 2019; 203:1001-1011. [DOI: 10.4049/jimmunol.1801110] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/09/2018] [Accepted: 06/10/2019] [Indexed: 12/17/2022]
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30
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Wang X, Ji C, Zhang H, Shan Y, Ren Y, Hu Y, Shi L, Guo L, Zhu W, Xia Y, Liu B, Rong Z, Wu B, Ming Z, Ren X, Song J, Yang J, Zhang Y. Identification of a small-molecule compound that inhibits homodimerization of oncogenic NAC1 protein and sensitizes cancer cells to anticancer agents. J Biol Chem 2019; 294:10006-10017. [PMID: 31101655 PMCID: PMC6597808 DOI: 10.1074/jbc.ra119.007664] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2019] [Revised: 05/09/2019] [Indexed: 12/13/2022] Open
Abstract
Nucleus accumbens-associated protein-1 (NAC1) is a transcriptional repressor encoded by the NACC1 gene, which is amplified and overexpressed in various human cancers and plays critical roles in tumor development, progression, and drug resistance. NAC1 has therefore been explored as a potential therapeutic target for managing malignant tumors. However, effective approaches for effective targeting of this nuclear protein remain elusive. In this study, we identified a core unit consisting of Met7 and Leu90 in NAC1's N-terminal domain (amino acids 1-130), which is critical for its homodimerization and stability. Furthermore, using a combination of computational analysis of the NAC1 dimerization interface and high-throughput screening (HTS) for small molecules that inhibit NAC1 homodimerization, we identified a compound (NIC3) that selectively binds to the conserved Leu-90 of NAC1 and prevents its homodimerization, leading to proteasomal NAC1 degradation. Moreover, we demonstrate that NIC3-mediated down-regulation of NAC1 protein sensitizes drug-resistant tumor cells to conventional chemotherapy and enhances the antimetastatic effect of the antiangiogenic agent bevacizumab both in vitro and in vivo These results suggest that small-molecule inhibitors of NAC1 homodimerization may effectively sensitize cancer cells to some anticancer agents and that NAC1 homodimerization could be further explored as a potential therapeutic target in the development of antineoplastic agents.
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Affiliation(s)
- XiaoHui Wang
- From the Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, 215123 Suzhou, Jiangsu, China
| | - Cheng Ji
- Department of Respiratory Medicine, First Affiliated Hospital, Soochow University, 215000 Suzhou, Jiangsu, China
| | - HongHan Zhang
- From the Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, 215123 Suzhou, Jiangsu, China
| | - Yu Shan
- Institute of Botany, Jiangsu Province and Chinese Academy of Science, 210014 Nanjing, Jiangsu, China
| | - YiJie Ren
- From the Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, 215123 Suzhou, Jiangsu, China
| | - YanWei Hu
- From the Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, 215123 Suzhou, Jiangsu, China
| | - LiangRong Shi
- Radiological Intervention Center, Department of Radiology, Xiangya Hospital, Central South University, 410013 Changsha, Hunan, China
| | - LingChuan Guo
- From the Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, 215123 Suzhou, Jiangsu, China
| | - WeiDong Zhu
- From the Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, 215123 Suzhou, Jiangsu, China
| | - YuJuan Xia
- From the Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, 215123 Suzhou, Jiangsu, China
| | - BeiJia Liu
- From the Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, 215123 Suzhou, Jiangsu, China
| | - ZiYun Rong
- From the Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, 215123 Suzhou, Jiangsu, China
| | - BiLian Wu
- From the Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, 215123 Suzhou, Jiangsu, China
| | - ZhiJun Ming
- From the Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, 215123 Suzhou, Jiangsu, China
| | - XingCong Ren
- Department of Cancer Biology and Toxicology, Markey Cancer Center, University of Kentucky College of Medicine, Lexington, Kentucky 40506
| | - JianXun Song
- Department of Microbial Pathogenesis and Immunology, Texas A&M University Health Science Center, College Station, Texas 77843, and
| | - JinMing Yang
- Department of Cancer Biology and Toxicology, Markey Cancer Center, University of Kentucky College of Medicine, Lexington, Kentucky 40506
| | - Yi Zhang
- From the Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, 215123 Suzhou, Jiangsu, China,
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31
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Shang J, Xia T, Han QQ, Zhao X, Hu MM, Shu HB, Guo L. Quantitative Proteomics Identified TTC4 as a TBK1 Interactor and a Positive Regulator of SeV-Induced Innate Immunity. Proteomics 2019; 18. [PMID: 29251827 DOI: 10.1002/pmic.201700403] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2017] [Revised: 12/06/2017] [Indexed: 12/20/2022]
Abstract
TBK1, STING, and MDA5 are important players within the antiviral innate immune response network. We mapped the interactome of endogenous TBK1, STING, and MDA5 by affinity enrichment MS in virally infected or uninfected THP-1 cells. Based on quantitative data of more than 2000 proteins and stringent statistical analysis, 58 proteins were identified as high-confidence interactors for at least one of three bait proteins. Our data indicated that TBK1 and MDA5 mostly interacted within preexisting protein networks, while STING interacted with different proteins with different viral infections. Functional analysis was performed on 17 interactors, and six were found to have functions in innate immune responses. We identified TTC4 as a TBK1 interactor and positive regulator of sendai virus-induced innate immunity.
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Affiliation(s)
- Jun Shang
- State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, Hubei, China
| | - Tian Xia
- State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, Hubei, China
| | - Qiang-Qiang Han
- State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, Hubei, China
| | - Xiaolu Zhao
- State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, Hubei, China
| | - Ming-Ming Hu
- Medical Research Institute, Wuhan University, Wuhan, Hubei, China
| | - Hong-Bing Shu
- State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, Hubei, China.,Medical Research Institute, Wuhan University, Wuhan, Hubei, China
| | - Lin Guo
- State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, Hubei, China
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32
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Targeting oncogenic transcriptional corepressor Nac1 POZ domain with conformationally constrained peptides by cyclization and stapling. Bioorg Chem 2018; 80:1-10. [DOI: 10.1016/j.bioorg.2018.05.024] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2018] [Revised: 05/10/2018] [Accepted: 05/23/2018] [Indexed: 12/13/2022]
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33
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NACC1, as a Target of MicroRNA-331-3p, Regulates Cell Proliferation in Urothelial Carcinoma Cells. Cancers (Basel) 2018; 10:cancers10100347. [PMID: 30248959 PMCID: PMC6210667 DOI: 10.3390/cancers10100347] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2018] [Revised: 09/12/2018] [Accepted: 09/20/2018] [Indexed: 12/20/2022] Open
Abstract
The nucleus accumbens-associated protein 1 (NACC1) is a transcription factor constitutively expressed in the urothelium, where it regulates cell growth, senescence, autophagy, and epithelial-mesenchymal transition. microRNA (miRNA) constitutes a class of small non-coding RNAs which are involved in cell proliferation, differentiation, and progression of tumors. miRNAs and their target molecules are utilized for molecular diagnosis of urothelial carcinoma. NACC1 is one of several putative target molecules of miR-331-3p, and is associated with cell proliferation in cancers such as prostate and cervical cancer. Functional experiments involving miR-331-3p and its target molecule NACC1 were conducted using the urothelial carcinoma (UC) cell lines, T24, UMUC6, and KU7. Furthermore, quantitative reverse transcription polymerase chain reaction and immunostaining were performed to evaluate the expression of NACC1 in UC derived from transurethral resection of bladder tumor (TUR-Bt) specimens. The methane thiosulfonate (MTS) assay revealed that cell proliferation was significantly reduced after transient transfection of miR-331-3p precursor and/or NACC1 siRNA in UC cells. Cell senescence via cell cycle arrest at the G1 phase was induced by NACC1 inhibition. On the other hand, suppression of NACC1 induced cell migration and invasion abilities. Immunohistochemical analysis of TUR-Bt specimens revealed that over 70% of UC cells presented strongly positive results for NACC1. In contrast, normal urothelial cells were weakly positive for NACC1. It was also found that NACC1 expression was lower in invasive UC cells than in non-invasive UC cells. Loss of NACC1 induced vessel invasion in invasive UC tissues. The present results indicate that NACC1 regulated by miR-331-3p contributes to cell proliferation, and is involved in cell migration and invasion. This suggests that NACC1 can serve as a potential target molecule for the prediction and prognosis of UC, and can contribute to effective treatment strategies.
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34
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Nakayama N, Sakashita G, Nariai Y, Kato H, Sinmyozu K, Nakayama JI, Kyo S, Urano T, Nakayama K. Cancer-related transcription regulator protein NAC1 forms a protein complex with CARM1 for ovarian cancer progression. Oncotarget 2018; 9:28408-28420. [PMID: 29983869 PMCID: PMC6033357 DOI: 10.18632/oncotarget.25400] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2018] [Accepted: 04/16/2018] [Indexed: 01/07/2023] Open
Abstract
NAC1 is a cancer-related transcription regulator protein that is overexpressed in various carcinomas, including ovarian, cervical, breast, and pancreatic carcinomas. NAC1 knock-down was previously shown to result in the apoptosis of ovarian cancer cell lines and to rescue their sensitivity to chemotherapy, suggesting that NAC1 may be a potential therapeutic target, but protein complex formation of intranuclear NAC1 in ovarian cancer cells remain poorly understood. In this study, analysis of ovarian cancer cell lysates by fast protein liquid chromatography on a sizing column showed that the NAC1 peak corresponded to an apparent molecular mass of 300–500 kDa, which is larger than the estimated molecular mass (58 kDa) of the protein. Liquid chromatography-tandem mass spectrometry analysis identified CARM1 as interacting with NAC1 in the protein complex. Furthermore, tissue microarray analysis revealed a significant correlation between CARM1 and NAC1 expression levels. Ovarian cancer patients expressing high levels of NAC1 and CARM1 exhibited poor prognosis after adjuvant chemotherapy. Collectively, our results demonstrate that high expression levels of NAC1 and its novel binding partner CARM1 may serve as an informative prognostic biomarker for predicting resistance to chemotherapy for ovarian cancer.
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Affiliation(s)
- Naomi Nakayama
- Department of Biochemistry, Shimane University School of Medicine, Izumo, Japan
| | - Gyosuke Sakashita
- Department of Biochemistry, Shimane University School of Medicine, Izumo, Japan
| | - Yuko Nariai
- Department of Biochemistry, Shimane University School of Medicine, Izumo, Japan
| | - Hiroaki Kato
- Department of Biochemistry, Shimane University School of Medicine, Izumo, Japan
| | - Kaori Sinmyozu
- Proteomics Support Unit, RIKEN Center for Developmental Biology, Kobe, Japan.,Current address: National Cerebral and Cardiovascular Center, Osaka, Japan
| | - Jun-Ichi Nakayama
- Graduate School of Natural Sciences, Nagoya City University, Nagoya, Japan
| | - Satoru Kyo
- Department of Obstetrics and Gynecology, Shimane University School of Medicine, Izumo, Japan
| | - Takeshi Urano
- Department of Biochemistry, Shimane University School of Medicine, Izumo, Japan
| | - Kentaro Nakayama
- Department of Obstetrics and Gynecology, Shimane University School of Medicine, Izumo, Japan
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35
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Liu Y, Song J, Zhang J, Yang L, Liu Z, Wang X. BTB/POZ domain-containing protein 7 is inversely associated with fibronectin expression in salivary adenoid cystic carcinoma. Oral Surg Oral Med Oral Pathol Oral Radiol 2018; 125:468-477. [DOI: 10.1016/j.oooo.2017.12.004] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2017] [Revised: 11/03/2017] [Accepted: 12/05/2017] [Indexed: 12/12/2022]
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36
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Ruan Y, He J, Wu W, He P, Tian Y, Xiao L, Liu G, Wang J, Cheng Y, Zhang S, Yang Y, Xiong J, Zhao K, Wan Y, Huang H, Zhang J, Jian R. Nac1 promotes self-renewal of embryonic stem cells through direct transcriptional regulation of c-Myc. Oncotarget 2018; 8:47607-47618. [PMID: 28548937 PMCID: PMC5564591 DOI: 10.18632/oncotarget.17744] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2017] [Accepted: 04/27/2017] [Indexed: 01/11/2023] Open
Abstract
The pluripotency transcriptional network in embryonic stem cells (ESCs) is composed of distinct functional units including the core and Myc units. It is hoped that dissection of the cellular functions and interconnections of network factors will aid our understanding of ESC and cancer biology. Proteomic and genomic approaches have identified Nac1 as a member of the core pluripotency network. However, previous studies have predominantly focused on the role of Nac1 in psychomotor stimulant response and cancer pathogenesis. In this study, we report that Nac1 is a self-renewal promoting factor, but is not required for maintaining pluripotency of ESCs. Loss of function of Nac1 in ESCs results in a reduced proliferation rate and an enhanced differentiation propensity. Nac1 overexpression promotes ESC proliferation and delays ESC differentiation in the absence of leukemia inhibitory factor (LIF). Furthermore, we demonstrated that Nac1 directly binds to the c-Myc promoter and regulates c-Myc transcription. The study also revealed that the function of Nac1 in promoting ESC self-renewal appears to be partially mediated by c-Myc. These findings establish a functional link between the core and c-Myc-centered networks and provide new insights into mechanisms of stemness regulation in ESCs and cancer.
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Affiliation(s)
- Yan Ruan
- Laboratory of Stem Cell and Developmental Biology, Department of Histology and Embryology, Third Military Medical University, Chongqing 400038, China.,Biomedical Analysis Center, Third Military Medical University, Chongqing 400038, China
| | - Jianrong He
- Laboratory of Stem Cell and Developmental Biology, Department of Histology and Embryology, Third Military Medical University, Chongqing 400038, China.,Department of Anesthesiology, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China
| | - Wei Wu
- Department of Cardiothoracic Surgery, Southwest Hospital, Third Military Medical University, Chongqing 400038, China
| | - Ping He
- Department of Cardiothoracic Surgery, Southwest Hospital, Third Military Medical University, Chongqing 400038, China
| | - Yanping Tian
- Laboratory of Stem Cell and Developmental Biology, Department of Histology and Embryology, Third Military Medical University, Chongqing 400038, China
| | - Lan Xiao
- Laboratory of Stem Cell and Developmental Biology, Department of Histology and Embryology, Third Military Medical University, Chongqing 400038, China
| | - Gaoke Liu
- Laboratory of Stem Cell and Developmental Biology, Department of Histology and Embryology, Third Military Medical University, Chongqing 400038, China
| | - Jiali Wang
- Laboratory of Stem Cell and Developmental Biology, Department of Histology and Embryology, Third Military Medical University, Chongqing 400038, China
| | - Yuda Cheng
- Laboratory of Stem Cell and Developmental Biology, Department of Histology and Embryology, Third Military Medical University, Chongqing 400038, China
| | - Shuo Zhang
- Laboratory of Stem Cell and Developmental Biology, Department of Histology and Embryology, Third Military Medical University, Chongqing 400038, China
| | - Yi Yang
- Experimental Center of Basic Medicine, College of Basic Medical Sciences, Third Military Medical University, Chongqing 400038, China
| | - Jiaxiang Xiong
- Experimental Center of Basic Medicine, College of Basic Medical Sciences, Third Military Medical University, Chongqing 400038, China
| | - Ke Zhao
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Beijing 100850, China
| | - Ying Wan
- Biomedical Analysis Center, Third Military Medical University, Chongqing 400038, China
| | - He Huang
- Department of Anesthesiology, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China
| | - Junlei Zhang
- Laboratory of Stem Cell and Developmental Biology, Department of Histology and Embryology, Third Military Medical University, Chongqing 400038, China
| | - Rui Jian
- Laboratory of Stem Cell and Developmental Biology, Department of Histology and Embryology, Third Military Medical University, Chongqing 400038, China
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37
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Karimi K, Esmailizadeh A, Wu DD, Gondro C. Mapping of genome-wide copy number variations in the Iranian indigenous cattle using a dense SNP data set. ANIMAL PRODUCTION SCIENCE 2018. [DOI: 10.1071/an16384] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
The objective of this study was to present the first map of the copy number variations (CNVs) in Iranian indigenous cattle based on a high-density single nucleotide polymorphism (SNP) dataset. A total of 90 individuals were genotyped using the Illumina BovineHD BeadChip containing 777 962 SNPs. The QuantiSNP algorithm was used to perform a genome-wide CNV detection across autosomal genome. After merging the overlapping CNV, a total of 221 CNV regions were identified encompassing 36.4 Mb or 1.44% of the bovine autosomal genome. The length of the CNV regions ranged from 3.5 to 2252.8 Kb with an average of 163.8 Kb. These regions included 147 loss (66.52%) and 74 gain (33.48%) events containing a total of 637 annotated Ensembl genes. Gene ontology analysis revealed that most of genes in the CNV regions were involved in environmental responses, disease susceptibility and immune system functions. Furthermore, 543 of these genes corresponded to the human orthologous genes, which involved in a wide range of biological functions. Altogether, 73% of the 221 CNV regions overlapped either completely or partially with those previously reported in other cattle studies. Moreover, novel CNV regions involved several quantitative trait loci (QTL)-related to adaptative traits of Iranian indigenous cattle. These results provided a basis to conduct future studies on association between CNV regions and phenotypic variations in the Iranian indigenous cattle.
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38
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Chen F, Yin Y, Yan Z, Cao K, Zhong K. NAC1 promotes the migration of prostate cancer cells and participates in osteoclastogenesis by negatively regulating IFNβ. Oncol Lett 2017; 15:2921-2928. [PMID: 29435019 PMCID: PMC5778845 DOI: 10.3892/ol.2017.7670] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2017] [Accepted: 11/23/2017] [Indexed: 12/14/2022] Open
Abstract
Nucleus accumbens-associated protein 1 (NAC1), a transcriptional co-regulator, is overexpressed in advanced prostate cancer. However, the NAC1-regulated transcriptome has not been completely explored. In the present study, the functional silencing of NAC1 blocked the migration of prostate cancer cells and suppress osteoclastogenesis. The present study also determined that NAC1 was overexpressed in the highly aggressive prostate cancer cell lines PC-3, DU-145 and LNCaP. NAC1 small interfering RNA treatment of DU-145 cells decreased cell migration, but interestingly had no significant effects on cell proliferation. Furthermore, microarray analysis showed that a group of genes may be associated with the development of prostate cancer after NAC1 knockdown, including interferon-β (IFNβ), which is reported to be involved in osteoclastogenesis, an important factor affecting bone metastasis. The mechanisms of NAC1 function were further explored by co-culture studies using PC-3 and RAW264.7 osteoclast precursor cells, which demonstrated that silencing NAC1 downregulated the genes associated with the activation of osteoclasts. Furthermore, it was revealed that NAC1 had the ability to affect the release of IFNβ into the extracellular environment. Together, these findings indicated that NAC1 promoted cell migration, and that NAC1 may have a key role in osteoclastogenesis.
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Affiliation(s)
- Fang Chen
- Department of Urology, The Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, P.R. China
| | - Yinghao Yin
- Department of Urology, The Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, P.R. China
| | - Zhifeng Yan
- Department of Urology, The Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, P.R. China
| | - Ke Cao
- Department of Oncology, The Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, P.R. China
| | - Kuangbiao Zhong
- Department of Urology, The Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, P.R. China
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39
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Kan H, Huang Y, Li X, Liu D, Chen J, Shu M. Zinc finger protein ZBTB20 is an independent prognostic marker and promotes tumor growth of human hepatocellular carcinoma by repressing FoxO1. Oncotarget 2017; 7:14336-49. [PMID: 26893361 PMCID: PMC4924719 DOI: 10.18632/oncotarget.7425] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2015] [Accepted: 01/29/2016] [Indexed: 12/17/2022] Open
Abstract
Zinc finger and BTB domain-containing 20 (ZBTB20) is a new BTB/POZ-domain gene and a member of the POK family of transcriptional repressors. Notably, the role of ZBTB20 and its underlying mechanisms involved in hepatocarcinogenesis are poorly investigated. In this study, the expression of ZBTB20 was significantly overexpressed in hepatocellular carcinoma (HCC) tissues. The positive expression of ZBTB20 was associated with large tumor size, high Edmondson-Steiner grading and advanced tumor-node-metastasis (TNM) tumor stage. Additionally, HCC patients with positive expression of ZBTB20 had a poorer 5-year survival. Multivariate analyses revealed that ZBTB20 overexpression was an independent prognostic factor for HCC. Gain- and loss-of-function experiments demonstrated that ZBTB20 promoted HCC cell viability, proliferation, tumorigenicity, and cell cycle progression. Mechanistically, Cyclin D1 and Cyclin E were increased, while p21 and p27 were decreased by ZBTB20 in HCC cells. FoxO1 was inversely correlated with ZBTB20 protein expression in the same cohort of HCC specimens. We further revealed that FoxO1 was transcriptionally repressed by ZBTB20 in HCC. Moreover, restoration of FoxO1 expression partially abrogated ZBTB20-induced HCC cell proliferation and growth entry in vitro and in vivo. Collectively, these results indicate that ZBTB20 may serve as a prognostic marker and promotes tumor growth of HCC via transcriptionally repressing FoxO1.
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Affiliation(s)
- Heping Kan
- Department of Hepatobiliary Surgery, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Yuqi Huang
- Department of Hepatobiliary Surgery, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Xianghong Li
- Department of Hepatobiliary Surgery, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Dingli Liu
- Department of Infectious Disease, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Jianjia Chen
- Department of Hepatobiliary Surgery, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Miaojiang Shu
- Department of Hepatobiliary Surgery, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
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40
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Ren YJ, Wang XH, Ji C, Guan YD, Lu XJ, Liu XR, Zhang HH, Guo LC, Xu QH, Zhu WD, Ming ZJ, Yang JM, Cheng Y, Zhang Y. Silencing of NAC1 Expression Induces Cancer Cells Oxidative Stress in Hypoxia and Potentiates the Therapeutic Activity of Elesclomol. Front Pharmacol 2017; 8:804. [PMID: 29163184 PMCID: PMC5681923 DOI: 10.3389/fphar.2017.00804] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2017] [Accepted: 10/25/2017] [Indexed: 12/28/2022] Open
Abstract
In order to survive under conditions of low oxygen, cancer cells can undergo a metabolic switch to glycolysis and suppress mitochondrial respiration in order to reduce oxygen consumption and prevent excessive amounts of reactive oxygen species (ROS) production. Nucleus accumbens-1 (NAC1), a nuclear protein of the BTB/POZ gene family, has pivotal roles in cancer development. Here, we identified that NAC1-PDK3 axis as necessary for suppression of mitochondrial function, oxygen consumption, and more harmful ROS generation and protects cancer cells from apoptosis in hypoxia. We show that NAC1 mediates suppression of mitochondrial function in hypoxia through inducing expression of pyruvate dehydrogenase kinase 3 (PDK3) by HIF-1α at the transcriptional level, thereby inactivating pyruvate dehydrogenase and attenuating mitochondrial respiration. Re-expression of PDK3 in NAC1 absent cells rescued cells from hypoxia-induced metabolic stress and restored the activity of glycolysis in a xenograft mouse model, and demonstrated that silencing of NAC1 expression can enhance the antitumor efficacy of elesclomol, a pro-oxidative agent. Our findings reveal a novel mechanism by which NAC1 facilitates oxidative stress resistance during cancer progression, and chemo-resistance in cancer therapy.
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Affiliation(s)
- Yi-Jie Ren
- Department of Pharmacology, College of Pharmaceutical Sciences and Department of Respiratory Medicine, First Affiliated Hospital, Soochow University, Suzhou, China
| | - Xiao-Hui Wang
- Department of Pharmacology, College of Pharmaceutical Sciences and Department of Respiratory Medicine, First Affiliated Hospital, Soochow University, Suzhou, China
| | - Cheng Ji
- Department of Pharmacology, College of Pharmaceutical Sciences and Department of Respiratory Medicine, First Affiliated Hospital, Soochow University, Suzhou, China
| | - Yi-Di Guan
- Department of Pharmacology, School of Pharmaceutical Sciences, Central South University, Changsha, China
| | - Xian-Jiu Lu
- Department of Gastrointestinal Surgery, Affiliated Nanhua Hospital, University of South China, Hengyang, China
| | - Xian-Rong Liu
- Department of Gastrointestinal Surgery, Affiliated Nanhua Hospital, University of South China, Hengyang, China
| | - Hong-Han Zhang
- Department of Pharmacology, College of Pharmaceutical Sciences and Department of Respiratory Medicine, First Affiliated Hospital, Soochow University, Suzhou, China
| | - Ling-Chuan Guo
- Department of Pharmacology, College of Pharmaceutical Sciences and Department of Respiratory Medicine, First Affiliated Hospital, Soochow University, Suzhou, China
| | - Qiong-Hua Xu
- Department of Pharmacology, College of Pharmaceutical Sciences and Department of Respiratory Medicine, First Affiliated Hospital, Soochow University, Suzhou, China
| | - Wei-Dong Zhu
- Department of Pharmacology, College of Pharmaceutical Sciences and Department of Respiratory Medicine, First Affiliated Hospital, Soochow University, Suzhou, China
| | - Zhi-Jun Ming
- Department of Pharmacology, College of Pharmaceutical Sciences and Department of Respiratory Medicine, First Affiliated Hospital, Soochow University, Suzhou, China
| | - Jin-Ming Yang
- Penn State Hershey Cancer Institute, The Pennsylvania State University College of Medicine, Hershey, PA, United States
| | - Yan Cheng
- Department of Pharmacology, School of Pharmaceutical Sciences, Central South University, Changsha, China
| | - Yi Zhang
- Department of Pharmacology, College of Pharmaceutical Sciences and Department of Respiratory Medicine, First Affiliated Hospital, Soochow University, Suzhou, China
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Ju T, Jin H, Ying R, Xie Q, Zhou C, Gao D. Overexpression of NAC1 confers drug resistance via HOXA9 in colorectal carcinoma cells. Mol Med Rep 2017; 16:3194-3200. [PMID: 28713930 PMCID: PMC5547960 DOI: 10.3892/mmr.2017.6986] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2015] [Accepted: 12/05/2016] [Indexed: 12/17/2022] Open
Abstract
Colorectal carcinoma (CRC) is one of the most common types of malignancy worldwide. Recently, neoadjuvant chemotherapy has become an important treatment strategy for CRC. However, treatment frequently fails due to the development of chemoresistance, which is a major obstacle for positive prognosis. However, the underlying mechanisms of chemoresistance remain unclear. The present study assessed the functions of nucleus accumbens-associated protein 1 (NAC1), an important transcriptional regulator, in CRC progression. Reverse transcription-quantitative polymerase chain reaction, western blot analysis and immunohistochemistry were performed to detect the expression levels of NAC1. It was identified that NAC1 was significantly overexpressed in CRC compared with non-tumorous tissues, indicating an oncogenic role. Following this, gain and loss of function analyses were performed in vitro to further investigate the function of NAC1. Cell viability and caspase-3/7 activity assays were used to assess chemotherapy-induced apoptosis. These results indicated that overexpression of NAC1 in CRC cells increased resistance to chemotherapy and inhibited apoptosis. Additionally, RNA interference-mediated knockdown of NAC1 restored the chemosensitivity of CRC cells. Furthermore, mechanistic investigation revealed that NAC1 increased drug resistance via inducing homeobox A9 (HOXA9) expression, and that knockdown of HOXA9 abrogated NAC1-induced drug resistance. In conclusion, the results of the present study demonstrated that NAC1 may be a critical factor in the development of chemoresistance, offering a potential novel target for the treatment of CRC.
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Affiliation(s)
- Tongfa Ju
- Department of Gastrointestinal and Anal Surgery, Hangzhou First People's Hospital, Nanjing Medical University, Hangzhou, Zhejiang 310006, P.R. China
| | - Huicheng Jin
- Department of Gastrointestinal and Anal Surgery, Hangzhou First People's Hospital, Nanjing Medical University, Hangzhou, Zhejiang 310006, P.R. China
| | - Rongchao Ying
- Department of Gastrointestinal and Anal Surgery, Hangzhou First People's Hospital, Nanjing Medical University, Hangzhou, Zhejiang 310006, P.R. China
| | - Qi Xie
- Department of Gastrointestinal and Anal Surgery, Hangzhou First People's Hospital, Nanjing Medical University, Hangzhou, Zhejiang 310006, P.R. China
| | - Chunhua Zhou
- Department of Gastrointestinal and Anal Surgery, Hangzhou First People's Hospital, Nanjing Medical University, Hangzhou, Zhejiang 310006, P.R. China
| | - Daquan Gao
- Department of Hematology, Hangzhou First People's Hospital, Nanjing Medical University, Hangzhou, Zhejiang 310006, P.R. China
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Nakayama K, Rahman M, Rahman MT, Nakamura K, Sato E, Katagiri H, Ishibashi T, Ishikawa M, Iida K, Razia S, Ishikawa N, Kyo S. Nucleus accumbens-1/GADD45GIP1 axis mediates cisplatin resistance through cellular senescence in ovarian cancer. Oncol Lett 2017; 13:4713-4719. [PMID: 28599472 PMCID: PMC5453174 DOI: 10.3892/ol.2017.6099] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2015] [Accepted: 01/04/2017] [Indexed: 01/25/2023] Open
Abstract
Nucleus accumbens-1 (NAC1), a nuclear factor belonging to the bric-a-brac-tramtrack-broad complex/pox virus and zinc finger gene family, is known to serve important roles in the proliferation and growth of tumor cells, and in chemotherapy resistance. However, the underlying molecular mechanisms through which NAC1 contributes to drug resistance remain unclear. In the present study, the role of NAC1 in drug resistance in ovarian cancer was investigated. NAC1 expression was markedly negatively associated with growth arrest and DNA-damage-inducible 45γ-interacting protein 1 (GADD45GIP1) expression in ovarian cancer. Increased NAC1 expression or decreased GADD45GIP1 expression was significantly associated with decreased progression-free survival (P=0.0041). Multivariate analysis demonstrated that NAC1/GADD45GIP1 expression was an independent prognostic factor of progression-free survival (P=0.0405). It was investigated whether cellular senescence was involved in NAC1-mediated resistance to cisplatin, a commonly used chemotherapeutic drug in the treatment of ovarian cancer. Treatment with cisplatin activated cellular senescence in ovarian cancer cell lines (SKOV3 and TOV-21G cells). Furthermore, knockdown of NAC1 by RNA interference significantly increased GADD45GIP1 expression and inhibited cisplatin-induced cellular senescence, resulting in increased cisplatin cytotoxicity in SKOV3 cells, which express increased levels of NAC1. To investigate whether the sensitizing effect of NAC1 inhibition on cisplatin-induced cytotoxicity may be attributed to the suppression of cellular senescence, the effects of NAC1 overexpression were assessed in TOV-21G cells, which do not express endogenous NAC1. Transfection with NAC1 in TOV-21G cells reduced the sensitivity of TOV-21G cells to cisplatin, indicating that suppression of cellular senescence was induced by GADD45GP1 activation. The results of the present study suggest that NAC1 is a negative regulator of cellular senescence and that NAC1-dependent suppression of senescence, mediated through GADD45GIP1, serves an important role in promoting cisplatin resistance. Therefore, the NAC1/GADD45GIP1 axis may be a potential target for the treatment of ovarian cancer, particularly in platinum-resistant cancers.
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Affiliation(s)
- Kentaro Nakayama
- Department of Obstetrics and Gynecology, Shimane University School of Medicine, Izumo, Shimane 6938501, Japan
| | - Munmun Rahman
- Department of Obstetrics and Gynecology, Shimane University School of Medicine, Izumo, Shimane 6938501, Japan
| | - Mohammed Tanjimur Rahman
- Department of Obstetrics and Gynecology, Shimane University School of Medicine, Izumo, Shimane 6938501, Japan
| | - Kohei Nakamura
- Department of Obstetrics and Gynecology, Shimane University School of Medicine, Izumo, Shimane 6938501, Japan
| | - Emi Sato
- Department of Obstetrics and Gynecology, Shimane University School of Medicine, Izumo, Shimane 6938501, Japan
| | - Hiroshi Katagiri
- Department of Obstetrics and Gynecology, Shimane University School of Medicine, Izumo, Shimane 6938501, Japan
| | - Tomoka Ishibashi
- Department of Obstetrics and Gynecology, Shimane University School of Medicine, Izumo, Shimane 6938501, Japan
| | - Masako Ishikawa
- Department of Obstetrics and Gynecology, Shimane University School of Medicine, Izumo, Shimane 6938501, Japan
| | - Kouji Iida
- Department of Obstetrics and Gynecology, Shimane University School of Medicine, Izumo, Shimane 6938501, Japan
| | - Sultana Razia
- Department of Obstetrics and Gynecology, Shimane University School of Medicine, Izumo, Shimane 6938501, Japan
| | - Noriyuki Ishikawa
- Department of Organ Pathology, Shimane University School of Medicine, Izumo, Shimane 6938501, Japan
| | - Satoru Kyo
- Department of Obstetrics and Gynecology, Shimane University School of Medicine, Izumo, Shimane 6938501, Japan
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Zhang Y, Ren YJ, Guo LC, Ji C, Hu J, Zhang HH, Xu QH, Zhu WD, Ming ZJ, Yuan YS, Ren X, Song J, Yang JM. Nucleus accumbens-associated protein-1 promotes glycolysis and survival of hypoxic tumor cells via the HDAC4-HIF-1α axis. Oncogene 2017; 36:4171-4181. [PMID: 28319066 PMCID: PMC5537617 DOI: 10.1038/onc.2017.51] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2016] [Revised: 01/25/2017] [Accepted: 01/27/2017] [Indexed: 12/25/2022]
Abstract
Nucleus accumbens-associated protein-1 (NAC1), a nuclear factor of the BTB/POZ gene family, has emerging roles in cancer. In this study, we identified the NAC1-HDAC4-HIF-1α axis as an important pathway in regulating glycolysis and hypoxic adaptation in tumor cells. We show that nuclear NAC1 binds to histone deacetylase type 4 (HDAC4), hindering phosphorylation of HDAC4 at Ser246 and preventing its nuclear export that leads to cytoplasmic degradation of the deacetylase. Accumulation of HDAC4 in the nuclei results in an attenuation of HIF-1α acetylation, enhancing the stabilization and transcriptional activity of HIF-1α and strengthening adaptive response of cells to hypoxia. We also show the role of NAC1 in promoting glycolysis in a mouse xenograft model, and demonstrate that knockdown of NAC1 expression can reinforce the antitumor efficacy of bevacizumab, an inhibitor of angiogenesis. Clinical implication of the NAC1-HDAC4-HIF-1α pathway is suggested by the results showing that expression levels of these proteins are significantly correlative in human tumor specimens and associated with the disease progression. This study not only reveals an important function of NAC1 in regulating glycolysis, but also identifies the NAC1-HDAC4-HIF-1α axis as a novel molecular pathway that promotes survival of hypoxic tumor cells.
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Affiliation(s)
- Y Zhang
- Department of Pharmacology, College of Pharmaceutical Sciences, First Affiliated Hospital, Soochow University, Jiangsu, China
| | - Y-J Ren
- Department of Pharmacology, College of Pharmaceutical Sciences, First Affiliated Hospital, Soochow University, Jiangsu, China
| | - L-C Guo
- Department of Pharmacology, College of Pharmaceutical Sciences, First Affiliated Hospital, Soochow University, Jiangsu, China
| | - C Ji
- Department of Pharmacology, College of Pharmaceutical Sciences, First Affiliated Hospital, Soochow University, Jiangsu, China
| | - J Hu
- Department of Pharmacology, College of Pharmaceutical Sciences, First Affiliated Hospital, Soochow University, Jiangsu, China
| | - H-H Zhang
- Department of Pharmacology, College of Pharmaceutical Sciences, First Affiliated Hospital, Soochow University, Jiangsu, China
| | - Q-H Xu
- Department of Pharmacology, College of Pharmaceutical Sciences, First Affiliated Hospital, Soochow University, Jiangsu, China
| | - W-D Zhu
- Department of Pharmacology, College of Pharmaceutical Sciences, First Affiliated Hospital, Soochow University, Jiangsu, China
| | - Z-J Ming
- Department of Pharmacology, College of Pharmaceutical Sciences, First Affiliated Hospital, Soochow University, Jiangsu, China
| | - Y-S Yuan
- Engineering Research Center of Cell and Therapeutic Antibody, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, China
| | - X Ren
- Department of Pharmacology and Microbiology and Immunology, The Penn State Hershey Cancer Institute, The Pennsylvania State University College of Medicine, Hershey, PA, USA
| | - J Song
- Department of Pharmacology and Microbiology and Immunology, The Penn State Hershey Cancer Institute, The Pennsylvania State University College of Medicine, Hershey, PA, USA
| | - J-M Yang
- Department of Pharmacology and Microbiology and Immunology, The Penn State Hershey Cancer Institute, The Pennsylvania State University College of Medicine, Hershey, PA, USA
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Schoch K, Meng L, Szelinger S, Bearden DR, Stray-Pedersen A, Busk OL, Stong N, Liston E, Cohn RD, Scaglia F, Rosenfeld JA, Tarpinian J, Skraban CM, Deardorff MA, Friedman JN, Akdemir ZC, Walley N, Mikati MA, Kranz PG, Jasien J, McConkie-Rosell A, McDonald M, Wechsler SB, Freemark M, Kansagra S, Freedman S, Bali D, Millan F, Bale S, Nelson SF, Lee H, Dorrani N, Goldstein DB, Xiao R, Yang Y, Posey JE, Martinez-Agosto JA, Lupski JR, Wangler MF, Shashi V. A Recurrent De Novo Variant in NACC1 Causes a Syndrome Characterized by Infantile Epilepsy, Cataracts, and Profound Developmental Delay. Am J Hum Genet 2017; 100:343-351. [PMID: 28132692 PMCID: PMC5294886 DOI: 10.1016/j.ajhg.2016.12.013] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2016] [Accepted: 12/22/2016] [Indexed: 02/08/2023] Open
Abstract
Whole-exome sequencing (WES) has increasingly enabled new pathogenic gene variant identification for undiagnosed neurodevelopmental disorders and provided insights into both gene function and disease biology. Here, we describe seven children with a neurodevelopmental disorder characterized by microcephaly, profound developmental delays and/or intellectual disability, cataracts, severe epilepsy including infantile spasms, irritability, failure to thrive, and stereotypic hand movements. Brain imaging in these individuals reveals delay in myelination and cerebral atrophy. We observe an identical recurrent de novo heterozygous c.892C>T (p.Arg298Trp) variant in the nucleus accumbens associated 1 (NACC1) gene in seven affected individuals. One of the seven individuals is mosaic for this variant. NACC1 encodes a transcriptional repressor implicated in gene expression and has not previously been associated with germline disorders. The probability of finding the same missense NACC1 variant by chance in 7 out of 17,228 individuals who underwent WES for diagnoses of neurodevelopmental phenotypes is extremely small and achieves genome-wide significance (p = 1.25 × 10-14). Selective constraint against missense variants in NACC1 makes this excess of an identical missense variant in all seven individuals more remarkable. Our findings are consistent with a germline recurrent mutational hotspot associated with an allele-specific neurodevelopmental phenotype in NACC1.
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Affiliation(s)
- Kelly Schoch
- Division of Medical Genetics, Department of Pediatrics, Duke Health, Durham, NC 27710, USA
| | - Linyan Meng
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Baylor Genetics, Houston, TX 77021, USA
| | - Szabolcs Szelinger
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - David R Bearden
- Division of Child Neurology, Department of Neurology, University of Rochester School of Medicine, Rochester, NY 14627, USA
| | - Asbjorg Stray-Pedersen
- Baylor-Hopkins Center for Mendelian Genomics, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Norwegian National Unit for Newborn Screening, Oslo University Hospital, 0424 Oslo, Norway
| | - Oyvind L Busk
- Section of Medical Genetics, Department of Laboratory Medicine, Telemark Hospital, 3710 Skien, Norway
| | - Nicholas Stong
- Institute for Genomic Medicine, Columbia University, New York, NY 10032, USA
| | - Eriskay Liston
- Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada
| | - Ronald D Cohn
- Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; Department of Pediatrics, University of Toronto, Toronto, ON M5G 1X8, Canada
| | - Fernando Scaglia
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Texas Children's Hospital, Houston, TX 77030, USA
| | - Jill A Rosenfeld
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
| | - Jennifer Tarpinian
- Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA
| | - Cara M Skraban
- Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Roberts Individualized Medical Genetics Center, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Department of Pediatrics, The Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Matthew A Deardorff
- Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Roberts Individualized Medical Genetics Center, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Department of Pediatrics, The Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Jeremy N Friedman
- Department of Pediatrics, University of Toronto, Toronto, ON M5G 1X8, Canada
| | - Zeynep Coban Akdemir
- Norwegian National Unit for Newborn Screening, Oslo University Hospital, 0424 Oslo, Norway
| | - Nicole Walley
- Division of Medical Genetics, Department of Pediatrics, Duke Health, Durham, NC 27710, USA
| | - Mohamad A Mikati
- Division of Pediatric Neurology, Department of Pediatrics, Duke Health, Durham, NC 27710, USA
| | - Peter G Kranz
- Division of Neuroradiology, Department of Radiology, Duke Health, Durham, NC 27710, USA
| | - Joan Jasien
- Division of Pediatric Neurology, Department of Pediatrics, Duke Health, Durham, NC 27710, USA
| | - Allyn McConkie-Rosell
- Division of Medical Genetics, Department of Pediatrics, Duke Health, Durham, NC 27710, USA
| | - Marie McDonald
- Division of Medical Genetics, Department of Pediatrics, Duke Health, Durham, NC 27710, USA
| | - Stephanie Burns Wechsler
- Division of Medical Genetics, Department of Pediatrics, Duke Health, Durham, NC 27710, USA; Division of Cardiology, Department of Pediatrics, Duke Health, Durham, NC 27710, USA
| | - Michael Freemark
- Division of Pediatric Endocrinology and Diabetes, Department of Pediatrics, Duke Health, Durham, NC 27710, USA
| | - Sujay Kansagra
- Division of Pediatric Neurology, Department of Pediatrics, Duke Health, Durham, NC 27710, USA
| | | | - Deeksha Bali
- Department of Pathology, Duke Health, Durham, NC 27710, USA
| | | | | | - Stanley F Nelson
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Hane Lee
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Clinical Genomics Center, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Naghmeh Dorrani
- Clinical Genomics Center, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - David B Goldstein
- Institute for Genomic Medicine, Columbia University, New York, NY 10032, USA
| | - Rui Xiao
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Baylor Genetics, Houston, TX 77021, USA
| | - Yaping Yang
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Baylor Genetics, Houston, TX 77021, USA
| | - Jennifer E Posey
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Baylor-Hopkins Center for Mendelian Genomics, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
| | - Julian A Martinez-Agosto
- Clinical Genomics Center, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Pediatrics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - James R Lupski
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Baylor-Hopkins Center for Mendelian Genomics, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA; Texas Children's Hospital, Houston, TX 77030, USA
| | - Michael F Wangler
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Baylor-Hopkins Center for Mendelian Genomics, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Neurological Research Institute, Texas Children's Hospital, Houston, TX 77030, USA.
| | - Vandana Shashi
- Division of Medical Genetics, Department of Pediatrics, Duke Health, Durham, NC 27710, USA.
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Wang Z, Jin K, Xia Y. Transcriptional analysis of the conidiation pattern shift of the entomopathogenic fungus Metarhizium acridum in response to different nutrients. BMC Genomics 2016; 17:586. [PMID: 27506833 PMCID: PMC4979188 DOI: 10.1186/s12864-016-2971-0] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2016] [Accepted: 07/27/2016] [Indexed: 12/14/2022] Open
Abstract
Background Most fungi, including entomopathogenic fungi, have two different conidiation patterns, normal and microcycle conidiation, under different culture conditions, eg, in media containing different nutrients. However, the mechanisms underlying the conidiation pattern shift are poorly understood. Results In this study, Metarhizium acridum undergoing microcycle conidiation on sucrose yeast extract agar (SYA) medium shifted to normal conidiation when the medium was supplemented with sucrose, nitrate, or phosphate. By linking changes in nutrients with the conidiation pattern shift and transcriptional changes, we obtained conidiation pattern shift libraries by Solexa/Illumina deep-sequencing technology. A comparative analysis demonstrated that the expression of 137 genes was up-regulated during the shift to normal conidiation, while the expression of 436 genes was up-regulated at the microcycle conidiation stage. A comparison of subtractive libraries revealed that 83, 216, and 168 genes were related to sucrose-induced, nitrate-induced, and phosphate-induced conidiation pattern shifts, respectively. The expression of 217 genes whose expression was specific to microcycle conidiation was further analyzed by the gene expression profiling via multigene concatemers method using mRNA isolated from M. acridum grown on SYA and the four normal conidiation media. The expression of 142 genes was confirmed to be up-regulated on standard SYA medium. Of these 142 genes, 101 encode hypothetical proteins or proteins of unknown function, and only 41 genes encode proteins with putative functions. Of these 41 genes, 18 are related to cell growth, 10 are related to cell proliferation, three are related to the cell cycle, three are related to cell differentiation, two are related to cell wall synthesis, two are related to cell division, and seven have other functions. These results indicate that the conidiation pattern shift in M. acridum mainly results from changes in cell growth and proliferation. Conclusions The results indicate that M. acridum shifts conidiation pattern from microcycle conidiation to normal conidiation when there is increased sucrose, nitrate, or phosphate in the medium during microcycle conidiation. The regulation of conidiation patterning is a complex process involving the cell cycle and metabolism of M. acridum. This study provides essential information about the molecular mechanism of the induction of the conidiation pattern shift by single nutrients. Electronic supplementary material The online version of this article (doi:10.1186/s12864-016-2971-0) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Zhenglong Wang
- Genetic Engineering Research Center, School of Life Sciences, Chongqing University, Chongqing, 400045, People's Republic of China.,Chongqing Engineering Research Center for Fungal Insecticide, Chongqing University, Chongqing, 400045, People's Republic of China.,Key Laboratory of Gene Function and Regulation Technologies under Chongqing Municipal Education Commission, Chongqing University, Chongqing, 400045, People's Republic of China
| | - Kai Jin
- Genetic Engineering Research Center, School of Life Sciences, Chongqing University, Chongqing, 400045, People's Republic of China.,Chongqing Engineering Research Center for Fungal Insecticide, Chongqing University, Chongqing, 400045, People's Republic of China.,Key Laboratory of Gene Function and Regulation Technologies under Chongqing Municipal Education Commission, Chongqing University, Chongqing, 400045, People's Republic of China
| | - Yuxian Xia
- Genetic Engineering Research Center, School of Life Sciences, Chongqing University, Chongqing, 400045, People's Republic of China. .,Chongqing Engineering Research Center for Fungal Insecticide, Chongqing University, Chongqing, 400045, People's Republic of China. .,Key Laboratory of Gene Function and Regulation Technologies under Chongqing Municipal Education Commission, Chongqing University, Chongqing, 400045, People's Republic of China.
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Nakayama N, Kato H, Sakashita G, Nariai Y, Nakayama K, Kyo S, Urano T. Protein complex formation and intranuclear dynamics of NAC1 in cancer cells. Arch Biochem Biophys 2016; 606:10-5. [PMID: 27424155 DOI: 10.1016/j.abb.2016.07.007] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2016] [Revised: 07/01/2016] [Accepted: 07/11/2016] [Indexed: 10/21/2022]
Abstract
Nucleus accumbens-associated protein 1 (NAC1) is a cancer-related transcription regulator protein that is also involved in the pluripotency and differentiation of embryonic stem cells. NAC1 is overexpressed in various carcinomas including ovarian, cervical, breast, and pancreatic carcinomas. NAC1 knock-down was previously shown to result in the apoptosis of ovarian cancer cell lines and to rescue their sensitivity to chemotherapy, suggesting that NAC1 may be a potential therapeutic target, but protein complex formation and the dynamics of intranuclear NAC1 in cancer cells remain poorly understood. In this study, analysis of HeLa cell lysates by fast protein liquid chromatography (FPLC) on a sizing column showed that the NAC1 peak corresponded to an apparent molecular mass of 300-500 kDa, which is larger than the estimated molecular mass (58 kDa) of the protein. Furthermore, live cell photobleaching analyses with green fluorescent protein (GFP)-fused NAC1 proteins revealed the intranuclear dynamics of NAC1. Collectively our results demonstrate that NAC1 forms a protein complex to function as a transcriptional regulator in cancer cells.
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Affiliation(s)
- Naomi Nakayama
- Department of Biochemistry, Shimane University School of Medicine, Izumo 693-8501, Japan
| | - Hiroaki Kato
- Department of Biochemistry, Shimane University School of Medicine, Izumo 693-8501, Japan
| | - Gyosuke Sakashita
- Department of Biochemistry, Shimane University School of Medicine, Izumo 693-8501, Japan
| | - Yuko Nariai
- Department of Biochemistry, Shimane University School of Medicine, Izumo 693-8501, Japan
| | - Kentaro Nakayama
- Department of Obstetrics and Gynecology, Shimane University School of Medicine, Izumo 693-8501, Japan
| | - Satoru Kyo
- Department of Obstetrics and Gynecology, Shimane University School of Medicine, Izumo 693-8501, Japan
| | - Takeshi Urano
- Department of Biochemistry, Shimane University School of Medicine, Izumo 693-8501, Japan.
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The hypusine cascade promotes cancer progression and metastasis through the regulation of RhoA in squamous cell carcinoma. Oncogene 2016; 35:5304-5316. [PMID: 27041563 DOI: 10.1038/onc.2016.71] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2015] [Revised: 12/22/2015] [Accepted: 12/22/2015] [Indexed: 12/20/2022]
Abstract
Metastasis is a critical factor contributing to poor prognosis in cancer, but the underlying mechanisms of metastasis are still poorly understood. We established a highly metastatic cell subline (HOC313-LM) derived from an oral squamous cell carcinoma cell line (HOC313) for uncovering the mechanisms of metastasis, and identified deoxyhypusine synthase (DHPS) as a metastasis-associated gene within the specific amplification at 19p13.2-p13.13 in HOC313-LM. DHPS-mediated hypusine-modification of eukaryotic translation factor 5A facilitated the translation of RhoA, resulting in the activation of the RhoA signaling pathway and leading to not only increased cell motility, invasion and metastasis of cancer cells in vitro, but also increased tumor growth in vivo. Moreover, the use of N1-Guanyl-1,7-diaminoheptane, a DHPS inhibitor, resulted in a significant decrease in tumor formation in vivo. In patients with esophageal squamous cell carcinoma (ESCC), overexpression of DHPS in ESCC tumors was significantly associated with worse recurrence-free survival, and correlated with distant metastasis. The elucidation of these molecular mechanisms within the hypusine cascade suggests opportunities for novel therapeutic targets in SCC.
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Abstract
Ovarian cancer, consisting mainly of ovarian carcinoma, is the most lethal gynecologic malignancy. Improvements in outcome for patients with advanced-stage disease are limited by intrinsic and acquired chemoresistance and by tumor heterogeneity at different anatomic sites and along disease progression. Molecules and cellular pathways mediating chemoresistance appear to be different for the different histological types of ovarian carcinoma, with most recent research focusing on serous and clear cell carcinoma. This review discusses recent data implicating various biomarkers in chemoresistance in this cancer, with focus on studies in which clinical specimens have been central.
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Affiliation(s)
- Ben Davidson
- a Department of Pathology , Oslo University Hospital, Norwegian Radium Hospital , Oslo , Norway.,b Faculty of Medicine , Institute of Clinical Medicine, University of Oslo , Oslo , Norway
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Malleshaiah M, Padi M, Rué P, Quackenbush J, Martinez-Arias A, Gunawardena J. Nac1 Coordinates a Sub-network of Pluripotency Factors to Regulate Embryonic Stem Cell Differentiation. Cell Rep 2016; 14:1181-1194. [PMID: 26832399 DOI: 10.1016/j.celrep.2015.12.101] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2015] [Revised: 10/19/2015] [Accepted: 12/23/2015] [Indexed: 12/15/2022] Open
Abstract
Pluripotent cells give rise to distinct cell types during development and are regulated by often self-reinforcing molecular networks. How such networks allow cells to differentiate is less well understood. Here, we use integrative methods to show that external signals induce reorganization of the mouse embryonic stem cell pluripotency network and that a sub-network of four factors, Nac1, Oct4, Tcf3, and Sox2, regulates their differentiation into the alternative mesendodermal and neuroectodermal fates. In the mesendodermal fate, Nac1 and Oct4 were constrained within quantitative windows, whereas Sox2 and Tcf3 were repressed. In contrast, in the neuroectodermal fate, Sox2 and Tcf3 were constrained while Nac1 and Oct4 were repressed. In addition, we show that Nac1 coordinates differentiation by activating Oct4 and inhibiting both Sox2 and Tcf3. Reorganization of progenitor cell networks around shared factors might be a common differentiation strategy and our integrative approach provides a general methodology for delineating such networks.
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Affiliation(s)
- Mohan Malleshaiah
- Department of Systems Biology, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115, USA.
| | - Megha Padi
- Biostatistics and Computational Biology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA
| | - Pau Rué
- Department of Genetics, University of Cambridge, Downing Street, Cambridge CB2 3EH, UK
| | - John Quackenbush
- Biostatistics and Computational Biology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA
| | | | - Jeremy Gunawardena
- Department of Systems Biology, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115, USA.
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Shan W, Li J, Bai Y, Lu X. miR-339-5p inhibits migration and invasion in ovarian cancer cell lines by targeting NACC1 and BCL6. Tumour Biol 2015; 37:5203-11. [PMID: 26553360 DOI: 10.1007/s13277-015-4390-2] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2015] [Accepted: 11/04/2015] [Indexed: 11/24/2022] Open
Abstract
This study aimed to explore the role of miR-339-5p in ovarian cancer. The expression of miR-339-5p in seven ovarian cancer cell lines (Hey, SKOV3, OVCAR5, SKOV3-IP, A2780, CAOV3, and OVCA433) was detected by quantitative real-time polymerase chain reaction (qRT-PCR). The miR-339-5p mimic and inhibitor were used to regulate its expression. Migration, invasion, and proliferation were examined. A bioinformatics analysis was used to predict targets, and a dual-luciferase reporter system was applied for validation, along with Western blot verification. Additionally, the association of miR-339-5p and its target genes with ovarian cancer was analyzed based on The Cancer Genome Atlas (TCGA) database. OVCAR5 and SKOV3 had the highest and lowest miR-339-5p expression, respectively. Inhibition of miR-339-5p expression increased the migration and invasion of OVCAR5 cells, while in SKOV3 cells, upregulated miR-339-5p attenuated the migration and invasion ability. Modulation of miR-339-5p had no effect on proliferation. The genes nucleus accumbens associated 1(BEN and BTB (POZ) domain containing) (NACC1) and B cell lymphoma-6 (bcl6) were validated to be targets of miR-339-5p. Clinically, patients with a high expression of NACC1 had a high risk in the survival analysis. miR-339-5p inhibits migration and invasion in ovarian cancer by targeting NACC1 and BCL6. miR-339-5p may be a biomarker of metastasis in ovarian cancer; NACC1 had a predictive value for ovarian cancer progression.
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Affiliation(s)
- Weiwei Shan
- Department of Gynecology, Obstetrics and Gynecology Hospital of Fudan University, 128 Shenyang Road in Yangpu District, Shanghai, 200011, China.,Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai, 200011, China
| | - Jun Li
- Department of Gynecology, Obstetrics and Gynecology Hospital of Fudan University, 128 Shenyang Road in Yangpu District, Shanghai, 200011, China.,Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai, 200011, China
| | - Yang Bai
- Department of Gynecology, Obstetrics and Gynecology Hospital of Fudan University, 128 Shenyang Road in Yangpu District, Shanghai, 200011, China.,Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai, 200011, China
| | - Xin Lu
- Department of Gynecology, Obstetrics and Gynecology Hospital of Fudan University, 128 Shenyang Road in Yangpu District, Shanghai, 200011, China. .,Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai, 200011, China.
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